Toxicokinetics and effects of fibrous and nonfibrous particles

Our plain-English summary of Toxicokinetics and effects of fibrous and nonfibrous particles, by G. Oberdörster (Inhalation Toxicology, 2002).

The study

• Author: G. Oberdörster
• Journal: Inhalation Toxicology
• Published: 2002;14(1):29-56
• Type of article: Review
• Cited by: 122 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO(2) produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity (PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counterbalance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level (NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers (>20 microm) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern-fast initial and slow final phase-it is essential that the slow phase of the retention kinetics of fibers longer than 20 microm is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.

In plain English

This article is a single-author review of published rat studies on how inhaled particles and fibers build up in and clear from the lung, and how this relates to lung tumors. It reported no new experiments. For poorly soluble, low-toxicity particles such as titanium dioxide, carbon black and diesel soot, the reviewed studies linked rat lung tumors to very high lung burdens that overwhelmed normal clearance. The author concluded that these high-dose tumors should not be used to predict risk at low doses. For fibers, the author focused on how long fibers longer than 20 µm persist in the lung. A table drawn from earlier work gave a slow-phase retention half-time of 1300 days in rats after inhalation for the amphiboles amosite and crocidolite, versus 87 days for a ceramic fiber. The author described chrysotile as less clear. Its long-fiber half-times appeared short, and tremolite contamination was raised as a possible factor in its effects. The author concluded that fibers of very low biopersistence should not be considered carcinogenic.

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 ("brief overview") of published animal studies, mainly chronic inhalation and fiber biopersistence studies in rats. No new data.
• Who was studied: Published experimental studies, mostly in rats. Mice and hamsters are mentioned for comparison. The review itself studied no animals or people.
• Exposure: Two groups of materials. (1) Poorly soluble, low-toxicity nonfibrous particles: titanium dioxide, carbon black, diesel particulate matter; crystalline silica as a cytotoxic comparison. (2) Fibers: amosite, crocidolite, chrysotile, refractory ceramic fiber and man-made vitreous fibers (MMVF), with emphasis on fibers longer than 20 µm.
• Main results:
  • In the reviewed rat studies of poorly soluble particles, the author interpreted lung particle overload as necessary but not sufficient for lung tumors. In the cited titanium dioxide study by Lee et al., only the highest exposure group developed lung tumors.
  • A cited meta-analysis by Valberg and Crouch (1999) pooled about 1100 rats from diesel exposure groups below overload levels and found a negative maximum likelihood estimate. The author read this as not supporting a role for diesel-associated PAH in rat lung tumors below overload.
  • In a table excerpted from Pott and Roller (1998), retention half-times for fibers longer than 20 µm in rats were as follows. Amphiboles (amosite, crocidolite) after inhalation: fast phase 17 days, slow phase 1300 days, weighted 466 days; after intratracheal instillation, 346 days. Ceramic fiber: 5, 87 and 41 days after inhalation; 233 days after instillation.
  • In a table partly based on Hesterberg et al. (1998), slow-phase half-times for fibers longer than 20 µm were listed with lung pathology. MMVF 34 had a half-time of 6 days with no fibrosis or tumors. Crocidolite (~1000 days) and amosite (more than 1000 days) were both marked for fibrosis and tumors. Chrysotile was listed as more than 100 days, with a question mark, also with fibrosis and tumors.
  • For chrysotile, the author wrote that reported retention half-times for long fibers appeared rather short. The author also wrote that chrysotile pathogenicity was reported as not different from the amphiboles, except for a lack of, or lower, potency for inducing mesothelioma.
• The authors' conclusion: On nonfibrous particles, the author concluded that high-dose rat lung tumors from poorly soluble particles should not be used for low-dose extrapolation, and that particle-associated organics do not add to the rat tumor response. On fibers, the author concluded that biopersistence is the key parameter, that fibers of very low biopersistence should not be considered carcinogenic, and that biopersistence assays should focus on the slow clearance phase of fibers longer than 20 µm.
• Limitations the authors state:
  • The author stated that the suggested differences between rat and human diesel particle exposures need to be verified.
  • The author stated that difficulty measuring the very fine fibrils of chrysotile may limit how precisely its retention half-times can be determined.
  • The author noted that contamination with amphiboles (tremolite) may be another problem contributing to the effects of chrysotile.
  • The author noted that intraperitoneal injection methods for measuring biopersistence raise questions about whether their results apply to the lung.
  • The author stated that biopersistence measurements alone should not be used to classify fibers and should be complemented by toxicity tests.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Fibrosis, Alveolar Macrophage, NOAEL, Lung Cancer, biopersistence, Carcinogenic, Biphasic Mesothelioma.

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