The Need for Both in Vitro and in Vivo Systems in Mutagenicity Screening

Rinkus, Stephen J.; Legator, Marvin S.

doi:10.1007/978-1-4613-3072-1_13

Cited by 16 publications

(6 citation statements)

References 223 publications

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“…There is a scarcity of information on the mutagenic activity of halogenated benzenes and naphthalenes and the data available are inconclusive (Table II) Cytogenetic analysis of human lymphocyte culture (119), Drosophila (120) as well as the bone marrow cells (121) and spermatogonia (121, 122) of rats exposed to relative high levels of several commercial products of PCBs showed no significant chromosomal aberrations. A number of sources (110,113,(123)(124)(125)(126) indicate that Aroclor 1254, several chlorinated biphenyls (4-chloro-, 2,4,2',4'-, 2,5,2",5'-and 3,4,3 \4'-tetrachloro-, and 2,4,6,2',4",6'-hexachloro-) and brominated biphenyls (2-bromo-, 3-bromo-, 4-brorao-, and hexabromo-) isomers are not mutagenic in strains TA1535, TA1537, TA98 or TA100 of Salmonella typhimurium (tested with or without liver microsomal activation).…”

Section: Mutagenicitymentioning

confidence: 99%

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a

Lai¹

1984

Journal of Environmental Science and Health. Part C: Environmen

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Section: Mutagenicitymentioning

confidence: 99%

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a

Lai¹

1984

Journal of Environmental Science and Health. Part C: Environmen

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“…A chromosomal test is included in the battery to provide detection of chemical effects at the highest level of genetic organization (8). In addition, such tests may detect nongenotoxic agents that operate through effects on DNA replication, chromosome separation, etc.…”

Section: In Vitro Short-term Testsmentioning

confidence: 99%

“…Thus, all these proposals include tests involving effects in whole organisms. The rationale for tests of this type has recently been reviewed by Rinkus & Legator (8).…”

Section: Introductionmentioning

confidence: 99%

“…A major achievement has been the introduction of techniques for the rapid identifi cation of mutagenic or carcinogenic potential, and a number of excellent monographs or reviews have dealt with this subject (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). General agreement now appears to exist that a battery of tests is required for toxicological evaluations in mass screening programs (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Systematic Carcinogen Testing Through the Decision Point Approach

Williams¹,

Weisburger²

1981

Annu. Rev. Pharmacol. Toxicol.

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“…Most of these tests were designed to detect and were validated with, these potent electrophilic compounds or their metabolites. As a consequence, certain classes of compounds that are less electrophilic may yield negative results or only weakly positive ones in short-term tests, particularly the Sulmonellulmicrosome assay [Rinkus and Legator, 1980;von Borstel and Mehta, 19821. Other compounds are known to act only at certain levels of genetic organization; for example, benzene acts as a clastogen but does not cause point mutations.…”

Section: Introductionmentioning

confidence: 99%

Implications of multiple mechanisms of carcinogenesis for short‐term testing

Harper¹,

Morris

1984

Teratog Carcinog Mutagen

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The attempt has been made recently to categorize carcinogens into two mechanistic types based on their mechanism of action: genotoxic (capable of reacting with and damaging DNA) and epigenetic (unable to damage DNA to any detectable extent). By requiring that a given chemical fit into one or the other of these narrowly defined categories for regulatory purposes, we are probably oversimplifying potential biological effects. In fact, based on our limited understanding of carcinogenic mechanisms, this artificial distinction should probably be abandoned in favor of a more precise statement of each chemical's mechanism or relative potency of initiating and promoting effects. Since the standard short-term tests by which carcinogenicity of chemicals is screened were designed to detect certain chemical classes with active electrophilic intermediates, weak or specialized carcinogens may be missed and may be assumed erroneously to be nongenotoxic. The mechanisms of carcinogenicity for such carcinogens may include particulate deposition, active radical formation, liver toxicity, and hormonal interactions. Not all of these secondary mechanisms depend upon a detectable level of binding to DNA, damage to DNA, or modification of the DNA sequence, even though they may demonstrate other characteristics of a complete carcinogen (that is, irreversibility and lack of a threshold). Certain agents have been labeled as epigenetic. However, a consideration of the literature on sample agents (diethylstilbestrol, asbestos, and urethane) reveals that these are not epigenetic carcinogens despite their being labeled as such. Agents with irreversibility and no threshold have initiating potential and, as such, are genotoxic, whereas carcinogens that are classified as nongenotoxic are largely agents that promote the growth of liver tumors. Even promotion can be a mechanistically specialized phenomenon. For example, some promoters are cytotoxic to the liver, but not all liver toxins are liver tumor promoters or liver carcinogens. Further, the carcinogens commonly labeled as epigenetic might cause a unique specialized genotoxicity not detected by common screening tests routinely used for detecting genotoxicity. If we assume that this unrecognized but necessary initiating potential is mediated by some specialized genotoxicity, extra care must be taken to establish a genuine lack of genotoxicity before an agent can be classified (and regulated) as a promoter (lacking the ability to initiate tumor growth but still enhancing tumor development).(ABSTRACT TRUNCATED AT 400 WORDS)

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The Need for Both in Vitro and in Vivo Systems in Mutagenicity Screening

Cited by 16 publications

References 223 publications

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a

Systematic Carcinogen Testing Through the Decision Point Approach

Implications of multiple mechanisms of carcinogenesis for short‐term testing

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The Need for Both in Vitro and in Vivo Systems in Mutagenicity Screening

Cited by 16 publications

References 223 publications

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effectsa

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effectsa

Systematic Carcinogen Testing Through the Decision Point Approach

Implications of multiple mechanisms of carcinogenesis for short‐term testing

Contact Info

Product

Resources

About

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a

Halogenated benzenes, naphthalenes, biphenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects^a