Dose-response relationship of fibrous dusts in intraperitoneal studies

Our plain-English summary of Dose-response relationship of fibrous dusts in intraperitoneal studies, by M. Roller, F. Pott, K. Kamino, et al (Environmental Health Perspectives, 1997).

The study

• Authors: M. Roller, F. Pott, K. Kamino, G.H. Althoff, B. Bellmann
• Journal: Environmental Health Perspectives
• Published: 1997;105 Suppl 5(Suppl 5):1253-6
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The relationship between the number of fibers injected intraperitoneally and the occurrence of peritoneal mesotheliomas in rats was investigated using data from a series of carcinogenicity studies with several fibrous dusts. Based on observed tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of dose-response relationships (parallel probit lines in probit analysis) cannot be rejected. In general, parallelism of probit lines is considered an indication of a common mode of action. Analysis of the shape of the dose-response relationship, with one apparent exception, shows virtually linear or superlinear behavior, i.e., from these data, there is no indication of a decrease in carcinogenic potency of an elementary carcinogenic unit at lower doses.

In plain English

This animal study analysed three experiments in which about 2000 Wistar rats were injected into the abdominal cavity with crocidolite or tremolite asbestos, eleven man-made vitreous fiber samples, non-fibrous silicon carbide, or saline, then observed for up to 30 months. Dose was the number of fibers longer than 5 micrometres, thinner than 2 micrometres and over five times longer than wide. Most fibrous dusts, including both asbestos types, produced statistically significantly increased mesothelioma frequencies, described as dose-dependent, though crocidolite was given at one dose only. Two of 433 saline or silicon carbide rats had mesotheliomas; none of 115 given 1000 mg silicon carbide did. Crocidolite and two other dusts were left out of the curve-shape analysis for lack of information. Excluding one more glass fiber (B-01-0.9), the remaining data did not deviate significantly from a model with a common, slightly superlinear shape (value 0.73). The authors concluded that the data gave no evidence of lower potency per dust unit at lower doses. They said this agreed with the assumption that the mechanism causing mesotheliomas here was specific to fibrous shape.

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: Animal experiment: statistical (probit and Weibull) analysis of dose-response data from a series of intraperitoneal injection carcinogenicity studies in rats
• Who was studied: About 2000 male and female Wistar rats in three experiments (studies from 1990 to 1992), observed for life up to 30 months
• Exposure: Intraperitoneal injection of crocidolite and tremolite asbestos, eleven man-made vitreous fiber samples, granular silicon carbide, or saline. Total dust mass per animal ranged from 0.5 mg (crocidolite) to 1000 mg. Dose was defined as the number of fibers longer than 5 micrometres, with diameter less than 2 micrometres and length-to-diameter ratio greater than 5 to 1.
• Main results:
  • With most fibrous dusts, including both asbestos types and different man-made vitreous fibers, frequencies of peritoneal mesothelioma were statistically significantly increased, and the authors described them as dose-dependent. Crocidolite was given at only one dose, so it gave no information on curve shape.
  • Among 433 rats given saline or granular silicon carbide (250 or 1000 mg), two had mesotheliomas
  • No mesotheliomas occurred in 45 female and 70 male rats given 1000 mg silicon carbide
  • The lower dose of MMVF21 produced a tumor frequency of 97%
  • With glass fiber B-01-0.9 included, the common-slope probit model showed a significant departure from the data (chi-squared 39.4, df 17, p = 0.002)
  • The test separating departure from parallelism from other lack of fit was not significant (F = 2.29, df 9 and 8, p = 0.13)
  • With B-01-0.9 excluded, there was no significant deviation from a model constrained to a common slope (chi-squared 14.4, df 13, p = 0.35)
  • The Weibull model, fitted under the constraint of a common shape, also showed no significant deviation (chi-squared 17.2, p = 0.19). Its estimated common shape parameter b was 0.73 (slightly superlinear).
  • Fitted separately, glass fiber B-01-0.9 had a sublinear curve (b = 2.4)
  • The authors stated that the data do not provide evidence of decreasing carcinogenic potency of a dust unit at lower doses
• The authors' conclusion: The authors concluded that their analysis agrees with the assumption that the mechanism responsible for the mesotheliomas in this experimental system is specific to the fibrous shape of the particles. They presented this as consistency with an assumption, not as an established mechanism.
• Limitations the authors state:
  • Data for crocidolite, R-Stone-Experimental 3 and MMVF21 gave too little information on curve shape and were left out of the analysis
  • Comparison with earlier (historical) injection studies needs care because positive animals were evaluated somewhat differently

Topics

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Peritoneal Mesothelioma, Carcinogenic.

Related studies

• Results of current intraperitoneal carcinogenicity studies with mineral and vitreous fibres — M. Roller, F. Pott, et al. (1996)
• Calcitonin gene-related peptide (CGRP) as hazard marker for lung injury induced by dusts — Y. Morimoto, A. Ogami, et al. (2007)
• Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study — D.M. Bernstein, B. Toth, et al. (2018)
• Mesothelioma dose response following intraperitoneal injection of mineral fibres — J.M. Davis, R.E. Bolton, et al. (1991)
• A trial on the quantitative risk assessment of man-made mineral fibers by the rat intraperitoneal administration assay using the JFM standard fibrous samples — S. Adachi, K. Kawamura, et al. (2001)
• Short-term inhalation and in vitro tests as predictors of fiber pathogenicity — R.T. Cullen, B.G. Miller, et al. (1997)

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