Mesothelioma dose response following intraperitoneal injection of mineral fibres

Our plain-English summary of Mesothelioma dose response following intraperitoneal injection of mineral fibres, by J.M. Davis, R.E. Bolton, B.G. Miller, et al (International Journal of Experimental Pathology, 1991).

The study

• Authors: J.M. Davis, R.E. Bolton, B.G. Miller, K. Niven
• Journal: International Journal of Experimental Pathology
• Published: 1991;72(3):263-74
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Free full text

Abstract

The relationship between injected dose and the development of peritoneal mesotheliomas has been examined in rats using the UTCC standard reference samples of chrysotile, crocidolite and amosite as well as a sample of fibrous erionite from Oregon. Doses injected into the peritoneal cavity ranged from 0.005 to 25 mg and with each dust a clear dose response was found. The proportion of animals developing tumours increased with the amount of dust injected while the tumour induction period was reduced. When times to death from mesothelioma were analysed using standard hazard models, erionite was the most carcinogenic dust by mass followed by chrysotile, amosite and crocidolite. The hazard slopes for erionite, chrysotile and crocidolite, over the range of doses examined, were parallel while the slope for amosite was shallower. The relative hazards for the various dust types were also examined with dose expressed as the number of injected fibres in a range of sizes as measured by SEM. No combination of fibre dimensions was found at which the hazard for the four dust types was equal although when dose was expressed as the number of long fibres injected (> 8 microns in length) the hazard slopes for chrysotile, crocidolite and amosite were relatively close. The hazard level of erionite remained well above the other dust types regardless of how the dose was expressed.

In plain English

In this animal experiment, groups of up to 48 rats each received a single injection into the abdominal (peritoneal) cavity. The injection contained chrysotile, crocidolite or amosite asbestos from UICC standard reference samples, or fibrous erionite from Oregon, at doses from 0.005 to 25 mg. The rats were then followed for life for peritoneal mesothelioma. With every dust, the proportion of rats developing tumours rose with dose, and tumours appeared sooner at higher doses. Measured by mass, erionite was the most carcinogenic, followed by chrysotile, amosite and crocidolite. For chrysotile, crocidolite and erionite, doubling the dose multiplied the hazard by 1.43. At 0.01 mg, chrysotile, amosite and erionite still produced some tumours but crocidolite did not. Erionite alone was tested at 0.005 mg, and it caused none. Counting fibres by size instead of weighing the dose never made the four dusts equal, although counting fibres longer than 8 micrometres brought chrysotile, crocidolite and amosite closer together. The authors stated that their data could not settle whether a safe threshold dose exists. They noted that injection skips the route inhaled fibres take through the lung.

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: single intraperitoneal injection of mineral fibres in rats at a range of doses, with animals kept for their full life-span (or killed when showing signs of disease)
• Who was studied: 8- to 10-week-old SPF laboratory rats of the AF/Han strain; group sizes per dose were up to 48 rats (Table 1), with smaller groups at the higher doses
• Exposure: Chrysotile (chrysotile A), crocidolite and amosite derived from the UICC standard reference samples, plus fibrous erionite from Oregon, suspended in saline and injected at doses from 0.005 to 25 mg; fibre numbers and sizes were measured by scanning electron microscopy
• Main results:
  • For each dust, the proportion of rats developing peritoneal mesothelioma increased with dose, and the tumour induction period was shorter at higher doses
  • In the hazard analysis by mass of dust, erionite was the most carcinogenic, followed by chrysotile, amosite and crocidolite
  • For chrysotile, crocidolite and erionite, doubling the mass dose multiplied the hazard by 1.43 (a 43% increase)
  • At equal mass doses, erionite was 1.25 times as hazardous as chrysotile, and crocidolite about a quarter as hazardous as chrysotile
  • For amosite, doubling the dose multiplied the hazard by about 1.27; at a 1 mg dose, chrysotile appeared nearly three times as hazardous as amosite
  • At 0.01 mg, chrysotile (4.3%), amosite (8.3%) and erionite (8.3%) still produced tumours in a small proportion of rats, but crocidolite (0.0%) did not
  • Erionite was the only dust tested at 0.005 mg (48 rats), and no tumours occurred
  • When dose was expressed as numbers of fibres of various sizes, no combination of fibre dimensions made the hazard of the four dusts equal; erionite stayed well above the others however dose was expressed
  • For fibres longer than 8 micrometres, the authors estimated that tumours would develop in at least 25% of rats if more than about 600,000 such fibres were injected (based on crocidolite, amosite and erionite at the lowest doses)
  • Far more long chrysotile fibres than long fibres of the other dusts were needed to produce the same proportion of tumours at the lowest doses
  • Tumour production appeared more closely related to long fibres thicker than 0.25 micrometres in diameter than to thinner long fibres
• The authors' conclusion: The authors found that, over the doses tested, the tumour response appeared linear on a log scale for all four dusts. They wrote that if this continued to much lower doses it would imply no safety threshold, but that longer induction periods at low doses might imply one. They stated that their study did not provide data to settle this question. They also noted that in this injection model crocidolite appeared less carcinogenic than amosite or chrysotile, unlike the human experience, possibly because injection bypasses how fibres travel through the lung.
• Limitations the authors state:
  • The authors stated that injection is unsuitable for extrapolating to inhalation doses
  • With groups of 48 rats, the absence of tumours at the lowest doses may only mean the hazard was about 1%, not that tumours would never occur
  • Chrysotile fibre diameters were measured before injection, but chrysotile splits into thinner fibrils in tissue, so the measured sizes may not reflect what acted in the body
  • Injection skips deposition in the lung and transport to the pleura, which may be the critical factor in human disease

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Peritoneal Mesothelioma, Chrysotile, Crocidolite, Amosite, erionite, Peritoneal Cavity, Carcinogenic.

Related studies

• Additional atypical malignant mesothelioma after intraperitoneal injection of mineral fibres in rats — K. Kamino, H. Ernst, et al. (1993)
• Dose-response relationship of fibrous dusts in intraperitoneal studies — M. Roller, F. Pott, et al. (1997)
• Acute and chronic effects of intraperitoneal injection of two types of asbestos in rats with a study of the histopathogenesis and ultrastructure of resulting mesotheliomas — M.L. Shin, H.I. Firminger (1973)
• An assessment of the fibrogenic potential of two refractory fibres by intraperitoneal injection in rats — G.H. Pigott, J. Ishmael (1981)
• Ultrastructure of mesothelial regeneration after intraperitoneal injection of asbestos fibres on rat omentum — S. Gonzalez, J. Friemann, et al. (1991)
• Results of current intraperitoneal carcinogenicity studies with mineral and vitreous fibres — M. Roller, F. Pott, et al. (1996)

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