Implications of multiple mechanisms of carcinogenesis for short-term testing

Our plain-English summary of Implications of multiple mechanisms of carcinogenesis for short-term testing, by B.L. Harper, D.L. Morris (Teratogenesis, Carcinogenesis, and Mutagenesis, 1984).

The study

• Authors: B.L. Harper, D.L. Morris
• Journal: Teratogenesis, Carcinogenesis, and Mutagenesis
• Published: 1984;4(6):483-503
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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)

In plain English

This 1984 article was a review and commentary, not a new experiment or study of people. The authors examined published research on how chemicals cause cancer. They questioned sorting carcinogens into 'genotoxic' types, which damage DNA, and 'epigenetic' types, which do not detectably damage DNA. They argued that standard short-term screening tests were built to detect certain reactive chemicals and may miss weaker or specialized carcinogens. They used diethylstilbestrol, asbestos and urethane as examples of agents that had been labeled epigenetic. For asbestos, the studies they cited reported that it was not mutagenic in bacterial cells and caused chromosome breakage in various hamster cell lines but not in rhesus monkeys or mice. A cited study also reported more sister chromatid exchanges in asbestos plant workers. The authors wrote that asbestos cancer risk in humans appears to rise linearly with dose at low doses, so no threshold can be calculated. They noted that some investigators argue a lung cancer threshold exists. The authors concluded that asbestos should not be considered nongenotoxic.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review and commentary on published literature about mechanisms of carcinogenesis and short-term (screening) tests; no new data were collected
• Who was studied: No study subjects of the authors' own. The authors reviewed published laboratory, animal and human studies on agents including diethylstilbestrol, asbestos, urethane, perchloroethylene, benzene, phenobarbital and DDT.
• Exposure: Chemical and physical carcinogens that had been labeled 'epigenetic', with diethylstilbestrol, asbestos and urethane as the main examples. The article refers to 'asbestos' in general, plus 'Asbestos and other fibers and foils' in its Table IV; the text does not specify fiber types.
• Main results:
  • From cited studies: asbestos was not mutagenic in bacterial cells but caused chromosome breakage in various hamster cell lines, though not in rhesus monkeys or mice.
  • From cited studies: asbestos did not induce sister chromatid exchange (SCE) in CHO-K1 cells, human fibroblasts or lymphoblasts. A study of asbestos plant workers reported an increased SCE frequency.
  • From a cited study: asbestos was detected as a mutagen in a human-CHO hybrid cell assay. Other cited work described asbestos acting as a carrier for chemicals such as benzo[a]pyrene.
  • The authors stated that asbestos carcinogenicity in humans appears to increase linearly with dose at low doses, so no threshold can be calculated.
  • The authors noted that some investigators argue for a lung cancer threshold, based on autopsy findings of relatively little asbestos-related lung cancer below a lung fiber burden printed as '0.5-1 x lo6 fiberdg' (apparently 0.5 to 1 million fibers per gram of lung tissue). This level was described as the upper limit for people not exposed in the workplace.
  • The authors stated that asbestos does not cause bronchogenic carcinoma in animals. Animal mesothelioma was described as dose responsive, possibly with a statistical threshold.
  • The authors also reviewed literature on diethylstilbestrol and urethane. They concluded that diethylstilbestrol is genotoxic in some short-term tests and that urethane appears to act through a covalent reaction with DNA.
• The authors' conclusion: The authors concluded that asbestos should not be considered nongenotoxic. In their view, not understanding its mechanism does not justify labeling it epigenetic or assuming a threshold. More generally, they preferred to assume that complete carcinogens of unknown mechanism are genotoxic.
• Limitations the authors state:
  • The authors noted that large groups exposed at the lowest asbestos doses are difficult to obtain. They also noted that little is known about how fibers and dusts relate to phagocytosis, inflammation, fibrosis and malignancy.
  • The authors stated that autopsy fiber-burden findings have been hard to standardize, that tumors are distributed unevenly within the lung lobes, and that the findings cannot be confirmed in animals.
  • The authors acknowledged that the mechanism of asbestos clastogenicity or carcinogenicity is not understood.
  • The authors stated that no completely satisfactory battery of short-term tests has been devised.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Carcinogenic, Deposition, Genotoxicity.

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