Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose

Our plain-English summary of Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose, by G. Oberdörster (Environmental Health Perspectives, 1997).

The study

• Author: G. Oberdörster
• Journal: Environmental Health Perspectives
• Published: 1997;105 Suppl 5(Suppl 5):1347-55
• Type of article: Review
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. The influence of high experimental doses on tumor development has been recognized for some time and has led to the concept of maximum tolerated dose (MTD) for dose selection, with the highest dose being at the MTD. Exposure at the MTD should ensure that the animals are sufficiently challenged while at the same time the animal's normal longevity is not altered from effects other than carcinogenicity. A characteristic of exposure-dose-response relationships for chronically inhaled particles is that lung tumors are significantly increased only at high exposure levels, and that lung tumors are seen in rats only but not in mice or hamsters. This lung tumor response in rats is thought to be secondary to persistent alveolar inflammation, indicating that the MTD may have been exceeded. Thus, mechanisms of toxicity and carcinogenicity may be dose dependent and may not operate at lower doses that humans normally experience. Despite awareness of this problem, carcinogenicity bioassays that evaluate particulate compounds in rodents have not always been designed with the MTD concept in mind. This is due to several problems associated with determining an appropriate MTD for particle inhalation studies. One requirement for the MTD is that some toxicity should be observed. However, it is difficult to define what degree of toxic response is indicative of the MTD. For particle inhalation studies, various noncancer end points in addition to mortality and body weight gain have been considered as indicators of the MTD, i.e., pulmonary inflammation, increased epithelial cell proliferation, increased lung weight, impairment of particle clearance function, and significant histopathological findings at the end of a subchronic study. However, there is no general agreement about quantification of these end points to define the MTD. To determine whether pulmonary responses are indicative of the MTD, we suggest defining an MTD based on results of a multidose subchronic and chronic inhalation study with a known human particulate carcinogen, e.g., asbestos or crystalline silica. Quantification of effects in such a study using the noncancer end points listed above would identify a dose level without significant signs of toxicity at the end of the subchronic study. If this dose level still results in significant lung tumor incidence at the end of the chronic study. We will have a sound basis for characterizing the MTD and justifying its use in future particle inhalation studies. Also, a better understanding of cellular and molecular mechanisms of particle-induced lung tumors is needed to support the MTD concept.

In plain English

This article was a brief review of chronic inhalation studies in rodents. It examined how the highest test dose, the maximum tolerated dose (MTD), should be chosen. The author listed fibrous particles that had caused lung tumors in rats, including amosite, anthophyllite, chrysotile, crocidolite and tremolite. The list also included nonfibrous particles such as quartz, talc, carbon black and titanium dioxide. Summarizing earlier work, the author stated that poorly soluble particles of low toxicity caused lung tumors in rats only at high lung burdens, greater than 1 mg/g of lung. Lung tumors had not been observed in mice and hamsters after chronic high-level exposures to nonfibrous particles of low solubility. The author described chronic lung inflammation as central to a suggested mechanism in rats, but said it is not known whether this operates in humans. The author concluded that no suitable definition of the MTD for particle inhalation studies existed. To set one, the author proposed a multidose rat study with a known human carcinogen, long amosite asbestos or crystalline silica, described as only a brief outline.

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: narrative review with a proposed study design; no new experimental data
• Who was studied: previously published chronic inhalation studies in rodents (mainly rats, also mice and hamsters) with fibrous and nonfibrous particles
• Exposure: Inhaled particles that caused lung tumors in rats. Fibrous: amosite, anthophyllite, chrysotile, crocidolite, palygorskite, potassium titanate, refractory ceramic fiber, silicon carbide, tremolite. Nonfibrous: antimony trioxide, carbon black, coal dust, diesel soot, nickel oxide, nickel subsulfide, oil shale, quartz, talc, titanium dioxide, volcanic fly ash.
• Main results:
  • From the reviewed data, the author stated that the retained lung burden leading to lung tumors in rats varies with particle cytotoxicity, size and shape, but is greater than 1 mg/g of lung for low-toxicity particles.
  • In the earlier 2-year rat studies cited, tumor-associated lung burdens were 665 mg per rat lung for pigment grade titanium dioxide (Lee et al.) and 39 mg for ultrafine titanium dioxide (Heinrich et al.).
  • In a cited comparison by Driscoll of rat lung tumor response across particle studies, only retained particle surface area (not mass) showed a highly significant correlation with tumors.
  • Unlike rats, mice and hamsters had not shown lung tumors after chronic high-level exposures to nonfibrous particles of low solubility.
  • The only chronic inhalation study in mice with fibers, using chrysotile, found both lung tumors and mesotheliomas.
  • In a cited 2-year diesel exhaust study in rats, the mid concentration (3.5 mg/m3) showed lung lavage neutrophils of about 10% at 6 months, rising to 40% at 12 months. The author used this to argue that a 3-month study may not predict the MTD for a 2-year study.
  • The proposed validation study would expose male and female rats to three or four concentrations of long amosite (about 10 to 200 fibers/cm3, with about 20% of fibers longer than 20 micrometers) or crystalline silica (0.1 to 3 mg/m3).
• The authors' conclusion: The author concluded that no appropriate definition of the MTD for particle inhalation studies was available. The author proposed calibrating one with a chronic rat study of a known human particulate carcinogen. If such a carcinogen does not cause tumors at lower doses, the author stated, the MTD concept for particle inhalation studies would have to be reconsidered.
• Limitations the authors state:
  • The author stated that it is not known whether the suggested inflammatory mechanism of tumor induction in rats also operates in humans.
  • The author described the proposed study as only an outline whose details had not been worked out.
  • The author noted that a threshold in the inflammation and mutation relationship would be difficult to verify.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Inflammation, Crystalline.

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