Nongenotoxic carcinogens in the regulatory environment

Our plain-English summary of Nongenotoxic carcinogens in the regulatory environment, by B.E. Butterworth (Regulatory Toxicology and Pharmacology, 1989).

The study

• Author: B.E. Butterworth
• Journal: Regulatory Toxicology and Pharmacology
• Published: 1989;9(3):244-56
• Type of article: Review
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The biological activity of many carcinogens is to directly induce mutational events, thereby altering the information encoded in the DNA. Short-term tests for potential carcinogens and risk assessment models generally rely on the assumption that the agent in question will operate through a genotoxic mechanism. However, carcinogenesis is a multistep process, and it is increasingly clear that the primary biological effect for many carcinogenic chemicals involves events other than direct DNA reactivity. For many experimental rodent models as well as human cancers, nongenotoxic mechanisms appear to be the driving force in the formation of tumors. Many of these nongenotoxic mechanisms are highly species-specific. Thus, it is increasingly important to ask if the rodent model applies to the human situation at all, in addition to the examination of appropriate, hypothetical, mathematical risk assessment models. More research is now being focused to better define the mechanisms by which the many distinctly different classes of nongenotoxic carcinogens are acting. This understanding will become the basis for new predictive assays and more realistic risk assessment models. If specific conditions are met, then a no observed effect level with a safety factor may be the most appropriate risk model for some carcinogens.

In plain English

This article is a review and commentary, presented at a 1988 regulatory toxicology meeting, with no new data. The author discussed carcinogens whose main action is not direct DNA damage ("nongenotoxic" carcinogens) and how their risk is assessed. In one paragraph, the author listed mineral fibers such as asbestos as "solid-state carcinogens", noting indications that people can be susceptible to cancer from specific asbestos types. The author also noted that fiber size and shape, the ability to produce aneuploidy (abnormal chromosome numbers), and local cell proliferation were being correlated with asbestos's cancer-causing activity. The author wrote that much more information was needed to know which properties a safe asbestos substitute should avoid. The author argued that different classes of carcinogens may need different risk models. The author suggested that, assuming chemically induced cell proliferation drives tumor formation, a no observed effect level with a safety factor could be used, with five listed properties as a prerequisite. The author acknowledged that the database needed to correlate the extent and duration of cell turnover with cancer potential, as a predictive assay, did not yet exist.

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, presented at the 4th Annual Meeting of the International Society of Regulatory Toxicology and Pharmacology (1988); no original data
• Who was studied: No population was studied directly; the article discusses classes of chemical and mineral carcinogens described in other published work, mostly rodent experiments
• Exposure: Nongenotoxic and other chemical carcinogens in general. Asbestos appears only in one paragraph on 'solid-state carcinogens' (mineral fibers such as asbestos); no specific fiber types are named
• Main results:
  • The author reported that other research was correlating properties of asbestos with its carcinogenic activity: fiber size and shape, the ability to produce aneuploidy, and the induction of local cell proliferation
  • The author stated that much more information was needed before it would be known which fiber properties to avoid when selecting a safe substitute for asbestos and man-made mineral fibers
  • The author stated that the most common biological activity of many nongenotoxic carcinogens is chemically induced cell division
  • The author suggested the no observed effect level approach could be employed if one assumes that chemically induced cell proliferation drives tumor formation.
  • As a prerequisite for that approach, the author required the chemical to show all five properties. First, it is not genotoxic in a battery of short-term tests. Second, over 500 mg/kg/day was needed to produce tumors. Third, tumors appeared only near the end of the study. Fourth, hyperplasia appeared in the target organ before tumors. Fifth, tumors appeared only in that single target organ.
• The authors' conclusion: The author concluded that different risk models may be appropriate for different classes of carcinogens. The author also concluded that concerns about whether the rodent model applies to humans are particularly large for nongenotoxic carcinogens because of their species specificity.
• Limitations the authors state:
  • The author stated that cell proliferation studies are labor intensive. The author also stated that the database needed to establish a correlation between the extent and duration of cell turnover and carcinogenic potential, for use as a predictive assay, did not yet exist.
  • The author stated that the distinction between genotoxic and nongenotoxic agents is often unclear

Topics

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

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