Effect of exposure route on potency of carcinogens

Our plain-English summary of Effect of exposure route on potency of carcinogens, by W.E. Pepelko (Regulatory Toxicology and Pharmacology, 1991).

The study

• Author: W.E. Pepelko
• Journal: Regulatory Toxicology and Pharmacology
• Published: 1991;13(1):3-17
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To compare the effectiveness of different exposure routes for the induction of cancer in experimental animals, the estimated dose associated with a 25% additional risk of cancer (RRD(25)) was calculated using a group of carcinogenic agents for which both inhalation and oral ingestion cancer bioassays were available. Comparisons were made of 14 agents in rats and 9 in mice. Seven of the nine compared in mice were also compared in rats. Among rats, 8 of 14 agents were more effective via the oral route, while 7 of 9 were more effective via the oral route in mice. The variation in RRD(25) values with route, however, was less than 10-fold for all the agents tested in mice and for 11 of 14 tested in rats. An overall difference in potency with route could not be detected statistically. In rats, differences in potency greater than 10-fold were found for asbestos, vinyl chloride, and hydrazine. In the case of asbestos, the agent was in the form of relatively insoluble particulate matter. The greater potency via inhalation is likely due to longer residence time of the particles in the deep lung than in the gut, allowing for a greater degree of particle dissolution with an accompanying increase in bioavailability. Vinyl chloride was generally tested by inhalation at doses high enough to saturate activation pathways, resulting in underestimates of low-dose potency. Many of the smaller potency differences with route, as well as those for hydrazine, were considered likely to be the result of variability in the design and/or quality of studies. It was concluded that, if the design and conduct of the experiments were adequate, if agents in the form of relatively insoluble particulate matter are eliminated, and if corrections are made to account for incomplete activation, then large errors during route extrapolation are unlikely to occur.

In plain English

This U.S. Environmental Protection Agency analysis compared cancer potency in laboratory animals exposed by mouth versus by inhalation. It used existing long-term studies with adequate data for both routes: 14 agents in rats, 9 in mice. Asbestos (chrysotile), the only non-organic agent, was compared only in rats. A computer model estimated the daily dose linked to a 25% added cancer risk. For most agents, oral and inhaled estimates were within tenfold, and statistical tests could not rule out equal potency by both routes. Asbestos was one of three exceptions in rats: 647 mg/day by mouth versus 5.9 mg/day by inhalation, a ratio of 109. The author suggested this was likely because the relatively insoluble particles stay longer in the deep lung than in the gut, allowing more to dissolve and become available to the body. The author concluded that large errors in route extrapolation are unlikely if relatively insoluble particulate agents are excluded, studies are adequate, and incomplete metabolic activation is corrected for. The author also flagged absorption, point-of-entry effects and liver breakdown, and noted the limited number of comparisons.

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: Comparative re-analysis of previously published and unpublished long-term animal cancer bioassays, using the Global 86 multistage model to estimate doses for oral versus inhalation exposure
• Who was studied: Rat and mouse cancer bioassay data sets for 14 agents tested in rats and 9 agents tested in mice, 7 of which were tested in both species
• Exposure: Oral (gavage, food or water) versus inhalation exposure to mostly organic chemicals. The one exception was asbestos, listed as chrysotile and compared in rats.
• Main results:
  • In rats, the estimated dose for a 25% added cancer risk (RRD25) for asbestos was 647 mg/day orally and 5.9 mg/day by inhalation, an oral/inhalation ratio of 109. At a 1% added risk (RRD01), the figures were 64 and 0.21 mg/day, a ratio of 305.
  • In rats, all agents except vinyl chloride, asbestos and hydrazine had oral and inhalation estimates within an order of magnitude of each other.
  • Among rats, 8 of 14 agents were more effective by the oral route. Among mice, 7 of 9 agents were more effective by the oral route.
  • In rats, the regression slope was 1.14 (95% confidence interval 0.33 to 3.37); omitting vinyl chloride and asbestos, it was 1.28 (0.35 to 1.79). Either way, equal potency by both routes (a slope of 1) could not be ruled out.
  • In mice, apart from dibromoethane, the oral/inhalation ratios ranged only from 0.6 to 2.
  • Of 29 adequately tested agents, 26 were positive for cancer by both routes. The only definite exceptions were relatively insoluble particulate matter.
  • The author considered the greater effectiveness of poorly soluble aerosols, including asbestos, by inhalation to be probably due to a longer residence time, which allows more of the material to dissolve.
  • The author also stated that it is important to determine whether absorption efficiency differs greatly with route, whether the agent acts systemically or at a portal of entry, and whether there are major first-pass effects.
• The authors' conclusion: The author concluded that large errors during route extrapolation are unlikely if three conditions are met: the experiments were adequately designed and conducted, agents in the form of relatively insoluble particulate matter are excluded, and corrections are made for incomplete metabolic activation. The author added that absorption efficiency, portal-of-entry action and first-pass effects should also be considered.
• Limitations the authors state:
  • The findings are based on a limited number of comparisons.
  • Route-related differences are understated when only agents that tested positive by both routes are considered.
  • No adequate comparisons were available for metals or other relatively insoluble particulate agents.
  • No mouse data were available for the two agents with the greatest route differences in rats.
  • The model's warning did not remove some data sets from doses known to saturate activation pathways.

Topics

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

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