Apparent synergy between chrysotile asbestos and N-nitrosoheptamethyleneimine in the induction of pulmonary tumours in rats

Our plain-English summary of Apparent synergy between chrysotile asbestos and N-nitrosoheptamethyleneimine in the induction of pulmonary tumours in rats, by P.T. Harrison, J.C. Heath (Carcinogenesis, 1988).

The study

• Authors: P.T. Harrison, J.C. Heath
• Journal: Carcinogenesis
• Published: 1988;9(12):2165-71
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Environmental carcinogenesis in man is widely accepted to be a multifactorial process, and in the causation of lung cancers it is suspected that low levels of systemic carcinogens may act synergistically with inhaled particulates so that some exposed individuals are at increased risk. In the present study the carcinogenic effects of low levels of industrially/environmentally significant particulate materials (chrysotile asbestos and metallic cadmium) and a putative systemic carcinogen, N-nitrosoheptamethyleneimine (NHMI), were investigated in the laboratory rat, using this as a model of potential human exposure. The overall lung tumour incidence rate in the groups of animals receiving chrysotile and NHMI together (8/50) or chrysotile, cadmium and NHMI together (6/44) was substantially higher than in the groups receiving chrysotile alone (1/86) or chrysotile and cadmium (1/94) or NHMI alone (2/48). The results demonstrated apparent synergy between chrysotile and NHMI in the induction of lung tumours. Incidence of pulmonary hyperplastic lesions paralleled the trend in tumour incidence. Cadmium had little or no influence on the incidence of either lung tumours or hyperplastic lesions. This study helps to evaluate further the role of asbestos in the causation of lung cancer. It is suggested that people who are or have been exposed to chrysotile asbestos may show a significantly elevated risk of lung cancer if concomitantly or subsequently exposed to tumour initiating agents.

In plain English

This was an animal experiment in female Lister hooded rats in Cambridge, UK. Some rats had one dose put into the windpipe: 2 mg of chrysotile asbestos, or 1.82 mg chrysotile mixed with 0.18 mg cadmium. Controls received saline only. Some rats also received ten weekly injections under the skin of N-nitrosoheptamethyleneimine (NHMI), a chemical known to cause lung tumours in rats. Rats were followed for up to 104 weeks. For epithelial or mixed-type lung tumours (benign plus malignant), the only type used in the analyses, rates were 0 of 47 in controls, 1.2% with chrysotile alone, 4.2% with NHMI alone, 16.0% (8 of 50) with chrysotile plus NHMI, and 13.6% (6 of 44) with chrysotile, cadmium and NHMI. Both combined groups had significantly more of these tumours than controls or chrysotile alone, but did not differ significantly from NHMI alone. The authors said their synergy test bordered on significance. Cadmium had little apparent effect. The authors concluded that people exposed to chrysotile may have increased lung cancer risk if also exposed to tumour-initiating substances.

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 (long-term carcinogenicity study in rats, with treatment groups and a saline control group)
• Who was studied: Female Lister hooded rats (Strangeways strain), 10 to 12 weeks old at the start, at Strangeways Research Laboratory, Cambridge, UK. Groups were set up with 50 or 100 animals. The numbers used for tumour analysis (alive at 250 days) were: control 47, NHMI 48, chrysotile 86, chrysotile + NHMI 50, chrysotile + cadmium 94, chrysotile + cadmium + NHMI 44. Rats were killed 104 weeks after first treatment unless they died or were killed earlier. Study dates are not given.
• Exposure: UICC standard reference chrysotile 'B' (Canadian), given once by intratracheal instillation. The chrysotile-only dose was 2 mg. The chrysotile/cadmium mixture contained 1.82 mg chrysotile and 0.18 mg cadmium. NHMI was given as 1 mg subcutaneous injections once a week for 10 weeks, beginning 6 weeks after instillation. Controls received saline only.
• Main results:
  • The tumour rates the authors analysed are for epithelial/mixed-type lung tumours (benign plus malignant) only. Hamartomas and stromal/mesodermal tumours were not included in the statistical analyses.
  • No lung tumours arose in the control group (0/47).
  • Chrysotile alone group: one malignant tumour (1.2% incidence). The authors found no evidence that small doses of chrysotile alone were carcinogenic in rat lung.
  • NHMI alone group: lung tumour rate of 4.2%, which the authors described as only slightly above background.
  • Groups given both chrysotile and NHMI had epithelial/mixed-type lung tumour rates of 16.0% (chrysotile + NHMI, 8/50) and 13.6% (chrysotile + NHMI + cadmium, 6/44).
  • Tumour incidence in both combined chrysotile + NHMI groups was significantly higher than in the control group (P less than 0.05) and than in the chrysotile alone group (P less than 0.01).
  • Tumour rates in the combined chrysotile + NHMI groups were not significantly different from the NHMI alone group (P greater than 0.05).
  • The statistical test for apparent (additive) synergy between chrysotile and NHMI gave z = 1.91, which the authors said borders on significance at the P = 0.05 level. A test for multiplicative synergy was positive but not confirmed statistically.
  • Focal epithelial hyperplastic lung lesions were found in 16 of 50 rats (32.0%) given chrysotile + NHMI and 14 of 45 (31.1%) given chrysotile + cadmium + NHMI. These rates were significantly higher than in controls (1 of 48, 2.1%; P less than 0.002) and than with NHMI alone (3 of 49, 6.1%; P less than 0.01).
  • Cadmium showed no evidence of an interactive effect with chrysotile or NHMI on lung hyperplasias or tumours.
  • One pulmonary malignant mesothelioma was recorded, in the chrysotile + cadmium + NHMI group.
• The authors' conclusion: The authors concluded that the potential significance for humans is that people who are or have been exposed to chrysotile asbestos may have an increased risk of lung cancer when also exposed to substances with tumour-initiating properties.
• Limitations the authors state:
  • The authors stated that the absence of a cadmium effect may reflect an antagonistic effect of chrysotile, or the use of inappropriate cadmium or NHMI doses.
  • In comparing this study with their earlier crocidolite study, the authors noted that NHMI alone produced different numbers of lung tumours in the two studies, and said further work is needed.
  • The authors stated that their results did not allow a detailed description of all stages of tumour development.

Topics

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

Medical terms in this study, explained in our Lexicon: Chrysotile, Carcinogenesis, Causation, Lung Cancer, Carcinogenic, Incidence.

Related studies

• Apparent synergy in lung carcinogenesis: interactions between N-nitrosoheptamethyleneimine, particulate cadmium and crocidolite asbestos fibres in rats — P.T. Harrison, J.C. Heath (1986)
• Effects of chrysotile asbestos on lung and pleural carcinogenesis of N-bis(2-hydroxypropyl)nitrosamine in rats — H. Katada, R. Higashiguchi, et al. (1983)
• Hyperplastic and Neoplastic Changes in the Lungs of Rats Treated Concurrently with Chrysotile Asbestos and N-Nitrosoheptamethyleneimine — P.T. Harrison, J.A. Hoskins, et al. (2000)
• Induction of pulmonary carcinoma in rats by chronic inhalation of dust from pulverized asbestos pipe covering — B.K. Leong, R.J. Kociba, et al. (1978)
• Garlic attenuates chrysotile-mediated pulmonary toxicity in rats by altering the phase I and phase II drug metabolizing enzyme system — M. Ameen, M.S. Musthapa, et al. (2003)
• Pulmonary effects in rats inhaling size-separated chrysotile asbestos fibres or p-aramid fibrils: differences in cellular proliferative responses — D.B. Warheit, M.A. Hartsky, et al. (1996)

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