Apparent synergy in lung carcinogenesis: interactions between N-nitrosoheptamethyleneimine, particulate cadmium and crocidolite asbestos fibres in rats

Our plain-English summary of Apparent synergy in lung carcinogenesis: interactions between N-nitrosoheptamethyleneimine, particulate cadmium and crocidolite asbestos fibres in rats, by P.T. Harrison, J.C. Heath (Carcinogenesis, 1986).

The study

• Authors: P.T. Harrison, J.C. Heath
• Journal: Carcinogenesis
• Published: 1986;7(11):1903-8
• Cited by: 14 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 and environmentally significant particulate materials (crocidolite 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 group of animals receiving crocidolite, cadmium and NHMI (14/45) was significantly higher than in the groups of animals receiving either crocidolite and cadmium together (2/51) or crocidolite and NHMI together (7/42). The results demonstrated an apparent synergy between cadmium and NHMI in the presence of crocidolite in the causation of lung cancer in rats, a finding which was confirmed statistically. This study helps to further evaluate and define the roles of asbestos and particulate cadmium in the causation of lung cancer. It is suggested that people who are exposed through occupation and/or environment to cadmium and asbestos and to low levels of systemic carcinogens may show a significantly elevated risk of lung cancer.

In plain English

This animal experiment used female hooded Strangeways-strain rats. Rats in four of five groups received one dose of UICC standard reference crocidolite asbestos into the windpipe, alone or mixed with powdered cadmium metal. Some then received 12 weekly injections of N-nitrosoheptamethyleneimine (NHMI). A fifth group received NHMI only. Malignant lung tumours occurred in 5 of 54 rats given crocidolite only, 2 of 51 given crocidolite plus cadmium, 7 of 42 given crocidolite plus NHMI, 14 of 45 given all three, and 10 of 58 given NHMI only. Most tumours were squamous carcinomas. Neither two-substance crocidolite group differed significantly from crocidolite alone. The three-substance group had significantly more tumours than the crocidolite plus cadmium, crocidolite plus NHMI and NHMI-only groups, and a test for 'apparent synergy' was just significant (P less than 0.05). The authors concluded that cadmium and NHMI appeared to interact when crocidolite was present. They suggested people exposed to cadmium, asbestos and low levels of substances such as N-nitroso compounds may show significantly elevated lung cancer risk. They noted 'apparent' synergy rests on simple incidence data.

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: Long-term animal experiment in rats comparing five treatment groups; the rats lived out their natural life-span or were killed when in extremis, and all were examined after death
• Who was studied: Female hooded rats of the Strangeways strain, 10 to 12 weeks old at treatment, at Strangeways Research Laboratory, Cambridge, UK. Effective group sizes were 54 (crocidolite alone), 51 (crocidolite plus cadmium), 42 (crocidolite plus NHMI), 45 (crocidolite plus cadmium plus NHMI) and 58 (NHMI alone). Rats dying within 12 weeks or not adequately examined were excluded. There was no cadmium-only group.
• Exposure: Four groups received a single intratracheal instillation of 2 mg of UICC standard reference crocidolite, or 2 mg of a crocidolite and powdered cadmium metal mixture (approximately 1.82 mg crocidolite and 0.18 mg cadmium). NHMI groups received 1 mg NHMI injected under the skin once a week for 12 weeks; in the crocidolite groups this began 6 weeks after instillation. The NHMI-only group received no crocidolite or cadmium.
• Main results:
  • The group given crocidolite plus cadmium plus NHMI had the highest overall malignant lung tumour rate: 31.1% (14 tumours among 45 rats).
  • The crocidolite plus NHMI group had a rate of 16.7% (7 of 42). The NHMI-only group had a rate of 17.2% (10 of 58).
  • In the crocidolite-only group the malignant lung tumour rate was approximately 9% (Table II: 5 of 54, 9.3%). The crocidolite plus cadmium group had approximately 4% (Table II: 2 of 51, 3.9%). The difference between these two groups was not statistically significant.
  • The higher rate in the crocidolite plus NHMI group than in the crocidolite-only group was not statistically significant.
  • The overall tumour rate in the crocidolite plus cadmium plus NHMI group was significantly greater than in the crocidolite plus cadmium group (P < 0.0005 in the Results section).
  • The crocidolite plus cadmium plus NHMI group also had a significantly higher rate than both the crocidolite plus NHMI group and the NHMI-only group.
  • Squamous carcinomas made up nearly 90% of all the malignant lung tumours (34 of 38 in Table I).
  • On Reif's additive test for apparent synergy, the observed rate exceeded the threshold (31.1 > 11.3). The multiplicative test was also positive (3.36 > 0.76).
  • A modified z-test of the apparent synergy among the crocidolite plus cadmium, crocidolite plus NHMI and crocidolite plus cadmium plus NHMI groups gave a just-significant result (P less than 0.05).
• The authors' conclusion: The authors concluded that apparent synergy occurred between cadmium and NHMI in the presence of crocidolite asbestos in causing lung cancer in rats. They suggested that people exposed through occupation and/or environment to cadmium and asbestos and to low levels of substances with initiating properties (e.g. N-nitroso compounds) may show significantly elevated lung cancer risk.
• Limitations the authors state:
  • The authors call the synergy 'apparent' in Reif's sense. It is based on simple incidence-rate data, could be invalidated if dose-response curves were available, and does not address underlying mechanisms.

Topics

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

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

Related studies

• Apparent synergy between chrysotile asbestos and N-nitrosoheptamethyleneimine in the induction of pulmonary tumours in rats — P.T. Harrison, J.C. Heath (1988)
• Effects of chrysotile asbestos on lung and pleural carcinogenesis of N-bis(2-hydroxypropyl)nitrosamine in rats — H. Katada, R. Higashiguchi, et al. (1983)
• On the mechanism of cogenotoxic action between ingested amphibole asbestos fibres and benzo[a]pyrene: I. Urinary and serum mutagenicity studies with rats — C. Varga, G. Horváth, et al. (1998)
• mRNA expression patterns in different stages of asbestos-induced carcinogenesis in rats — H. Sandhu, W. Dehnen, et al. (2000)
• Metal interactions in carcinogenesis: enhancement, inhibition — G.F. Nordberg, O. Andersen (1981)
• Lung mesothelial cell and fibroblast responses to pleural and alveolar macrophage supernatants and to lavage fluids from crocidolite-exposed rats — I.Y. Adamson, H. Prieditis, et al. (1997)

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