ABSTRACT
This article is in response to the challenge issued to the scientific community by the National Toxicology Program to predict the carcinogenicity potential of 30 chemicals previously selected for long-term carcinogenicity testing. Utilizing the available toxicologic, genetic, and structural information on 30 chemicals previously selected for long-term carcinogenicity testing, we predict that 16 chemicals (53%) would induce some indication of carcinogenic activity in rodents; we further predict that 10 chemicals (33%) would be associated with weak or equivocal carcinogenic responses, and another 4 (13%) would give no indication of carcinogenicity. Our level of certainty is indicated for many of these predictions. Nonetheless, we believe that most instances of guessing whether a chemical would eventually induce cancer in experimental animals and hence represent a carcinogenic hazard to humans are fraught with considerable uncertainty: uncertainty that can only be relieved by long-term testing for carcinogenicity in animals or by conducting an epidemiologic investigation of exposed individuals or groups. We further believe that the day may come when our predictive acumen will be upgraded to such an extent that we might eventually obviate cancer testing. Until then, and in the best interests of public health, however, we urge long term testing of chemicals in animals be continued, at increased pace.
Subject(s)
Carcinogenicity Tests , Carcinogens/toxicity , Animals , Mice , RatsABSTRACT
The selection process for chemicals tested in the rodent carcinogenicity bioassay has been biased toward chemicals suspected of potential carcinogenicity. Results from carcinogenicity bioassays of 400 chemicals tested by the National Cancer Institute/National Toxicology Program (NCI/NTP) were analyzed to determine the dependence of positive results on chemical selection criteria: those suspected of being carcinogenic and those selected based on large volumes produced and widespread exposures. Of these chemicals, 210 (52%) induced carcinogenicity in at least one organ of one sex of one species of the four sex/species groups typically used by NCI/NTP. Only 92 of the 400 chemicals (23%) were positive in two species and thus by international criteria are considered likely to pose a carcinogenic hazard to humans. A total of 267 chemicals (67%) were selected as suspect carcinogens, and 187 (68%) of these were carcinogenic. Suspect chemicals account for 86% of chemicals with at least one positive result and account for 90% of chemicals considered positive in two species. The International Agency for Research on Cancer (IARC) lists only 5 of the 400 chemicals as carcinogenic to humans (group 1) and 10 as probably carcinogenic to humans (group 2A). The majority (80%) of the 133 chemicals selected only on production/exposure considerations were not carcinogenic in animals, even when tested at the maximum tolerated (or minimally toxic) dose. Only 9 (6.8%) were positive in two species, and none is listed in IARC groups 1 or 2A. Thus, on the basis of our analyses we predict that less than 5-10% of the 75,000 chemicals in commercial use might be reasonably anticipated to be carcinogenic to humans.
Subject(s)
Carcinogens/adverse effects , Neoplasms, Experimental/chemically induced , Animals , Carcinogenicity Tests , Carcinogens/classification , Environmental Exposure/adverse effects , Humans , Mice , RatsABSTRACT
The a priori criteria used by the National Cancer Institute/National Toxicology Program (NCI/NTP) are described for 379 chemicals selected and evaluated for carcinogenic potential. We classified the chemicals according to exposure and structural categories and evaluated the predictive ability of the scientific selection criteria of chemicals suspected of being carcinogenic in advance of any study. Of the 379 chemicals, 253 (67%) were selected with a suspicion of carcinogenicity; 171 (68%) of these 253 chemicals induced cancer in at least one of the sex-species experiments. The other 126 (33%) chemicals were selected mainly, but not exclusively, on the basis of exposure considerations and production volumes; only 27 (21%) of these were judged to be positive. Overall, 198 (52%) of the 379 chemicals studied induced tumors in at least one organ of one sex of one species, but only 87 (23%) of these 379 chemicals were positive in both species and are considered most likely to present carcinogenic hazards to humans. Importantly, 78 (90%) of these 87 chemicals were selected with a prospective suspicion of carcinogenicity. Although the program has studied only a part of the "Universe of Chemicals" (defined as chemicals to which humans are exposed), the scientific data generated are essential for developing structure activity data bases of potentially hazardous chemical classes and for predicting the carcinogenicity of chemicals not yet studied. Thus, the bioassay program has had beneficial and crucial impacts on public health, as demonstrated by the use of these data by international, Federal, and State regulatory agencies to reduce or eliminate exposures to chemicals shown to be unequivocally carcinogenic in laboratory animals.
Subject(s)
Carcinogens/toxicity , Animals , Decision Making , Humans , National Institutes of Health (U.S.) , United StatesABSTRACT
The mutagenicity of 4 coffee flavor ingredients (chlorogenic acid, caffeic acid, pyrazine, and trigonelline) was evaluated in the Salmonella plate incorporation assay and mouse lymphoma L5178Y TK +/- assay. Two of the compounds, pyrazine and trigonelline, were negative in both assays. The other two compounds, caffeic acid and chlorogenic acid, were positive in the mouse lymphoma assay but negative in the Salmonella assay.
Subject(s)
Alkaloids/pharmacology , Caffeic Acids/pharmacology , Chlorogenic Acid/pharmacology , Cinnamates/pharmacology , Coffee/analysis , Pyrazines/pharmacology , Salmonella typhimurium/drug effects , Tumor Cells, Cultured/drug effects , Animals , Biotransformation , Chemical Phenomena , Chemistry , Cricetinae , Leukemia L5178/pathology , Male , Mesocricetus , Mice , Mutagenicity Tests/methods , Rats , Rats, Inbred F344ABSTRACT
A total of 27 dyes and related chemicals were tested for mutagenicity in both the Salmonella typhimurium plate-incorporation and FMN-modified assays as well as the mouse lymphoma TK+/- assay. Half of the compounds tested were monoazo dyes (14); the remainder consisted of disazo (3), aminotriphenylmethane derivatives (4), and other miscellaneous (6) color compounds. The results obtained in this study are compared with data from dyes of the same batch tested in other laboratories in the Salmonella plate-incorporation assay and in both in vitro and in vivo/in vitro UDS assays. Agreement of results from the various assays that could be compared (excluding results that were equivocal or indeterminate) ranged from 80 to 91%. Sufficient data were available to provide an overall index of in vitro activity for 15 chemicals; of these, 14 compounds could be compared to and agreed with reports of their carcinogenic potential in the literature.
Subject(s)
Coloring Agents/pharmacology , Salmonella typhimurium/drug effects , Tumor Cells, Cultured/drug effects , Animals , Cricetinae , Leukemia L5178/enzymology , Leukemia L5178/genetics , Male , Mesocricetus , Mice , Mutagenicity Tests , Neoplasm Proteins/genetics , Rats , Rats, Inbred F344 , Thymidine Kinase/genetics , Tumor Cells, Cultured/enzymologyABSTRACT
To aid in the selection of chemical candidates for in vivo tests, the mutagenicity of 5 thiazole compounds was evaluated in the Salmonella plate incorporation assay and mouse lymphoma L5178Y TK+/- assay. Two of the compounds, 2-thiazolamine and 3-methyl-5-isothiazolamine, were positive in both assays; and one, thiazole, was negative. With the other 2 compounds the results were nonconcordant: 5-phenyl-2,4-thiazolediamine was negative in the Salmonella assay but positive in the mouse lymphoma assay, and C.I. Basic Red 29 was positive in the Salmonella assay while the response in the mouse lymphoma assay was considered equivocal.
Subject(s)
Mutation/drug effects , Thiazoles/toxicity , Animals , Biotransformation , Cell Survival/drug effects , Cells, Cultured , Lymphoma/enzymology , Mice , Microsomes, Liver/metabolism , Mutagenicity Tests , Salmonella typhimurium/drug effects , Thymidine Kinase/geneticsSubject(s)
Neoplasms, Experimental/chemically induced , Animals , Drug Evaluation, Preclinical , Female , Male , Mice , RatsABSTRACT
Aromatic analogues of (all-E)- and 13(Z)-retinoic acids have been synthesized as potential chemopreventive agents for the treatment of epithelial cancer. In the E series, (1E,3E)-1-(4-carboxyphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3- butadiene (7a), its ethyl ester 5a, and the epoxy ethyl ester 14 displayed excellent activity in the assay for the inhibition of tumor promotor-induced mouse epidermal ornithine decarboxylase, while (1E,3E)-1-(4-carboethoxy-3-methylphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadiene (5b) was inactive. The 13(Z) analogues, (E)-1-(2-carboxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-he xatriene (19) and (E)-1-(2-hydroxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-he xatriene (27), had minimal activity.
Subject(s)
Tretinoin/analogs & derivatives , Animals , Mice , Phorbol Esters/metabolism , Skin/drug effects , Skin/metabolism , Tretinoin/chemical synthesis , Tretinoin/pharmacologyABSTRACT
Analogues of retinoic acid have been synthesized as potential chemopreventive agents against epithelial cancer. Ethyl (E)-9-(2-norbornenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (9), (E)-3,7-dimethyl-9-(2-ethyl-6,6-dimethyl-1-cyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid (25), and 2-(2'-methoxyethoxy)ethyl retinoate (26) displayed good activity in the inhibition of tumor promoter-induced mouse epidermal ornithine decarboxylase assay. (E)-1-(3-Acetoxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)hexa1,3,5 -triene (34) had low activity. (E)-5-[2,6-Dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)octa-1,3,5,7-tetraen-1 -yl]tetrazole (40) was inactive.
