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THE DAVID HORROBIN CONTROVERSY
THE BENZODIAZEPINE / CANCER DEBATE
Ray Nimmo, March 15, 2012
David Frederick Horrobin (1939-2003) was a medical researcher, professor, author and editor. Born in Bolton, England, he studied medicine at Balliol College, Oxford, obtaining degrees in both medicine and surgery and earned a doctorate in neurophysiology and neuroendocrinology. On completing his pre-clinical work, Dr Horrobin became a fellow of Magdalen College in 1963. Following participation in the Flying Doctor Service in east Africa, Dr Horrobin was appointed as professor and chairman of medical physiology at Nairobi University in Kenya. In 1972, he moved to the University of Newcastle upon Tyne, where he was appointed as a reader in medical physiology. In 1975, he became a professor of medicine at the University of Montreal. Dr Horrobin was the author of over 800 publications, including around 500 scientific papers.
In the late 1970s / early 1980s while at the University of Montreal Professor Horrobin conducted research into a possible link between Valium (diazepam) and cancer and published his findings: 'Diazepam Said To Be a Tumour Promotor at Therapeutic Levels', CFP News, February 1981, pp192-194 and 'The possible effect of diazepam on cancer development and growth', Horrobin, D. F. and Trosko, J. E., Med Hypoth 1981; 7: 117-127.
A report on Dr Horrobin's work published in the Globe and Mail sparked a row which was conducted in letters to the editors of The Lancet and New Scientist. Dr Horrobin claimed he subsequently lost his £20,000-a-year (around £100,000 today) job because of his controversial research into the potential carcinogenic effects of diazepam.
Below are a sample of news articles published in 1981. See also some more recent research headed by Dr Daniel Kripke which explores the link between benzodiazepines / Z drugs and mortality including cancer.
CANADA INVESTIGATES THE VALIUM-CANCER LINK - New Scientist, March 26 1981
Canadian government scientists are to carry out the first full investigation of a controversial claim that the tranquilliser diazepam - better known as Valium - speeds up the growth of cancer.
The £10 000 project will last a year, and will involve studies of existing work by British, American and Canadian scientists. The Health Protection Branch of the Canadian government says it will also conduct bacterial and animal tests.
Concern over the drug, which is the most widely-used tranquilliser in the world, arose when Dr David Horrobin, a British scientist based in Montreal, published the results of animal tests which he claimed showed that diazepam speeded up the growth of tumours (New Scientist, 8 January, p 80).
Horrobin says the Canadian medical research authorities have refused him funds for further studies and that he lost his £20 000-a-year research job because of his work with diazepam. He claims that when he fed diazepam to rats with implanted breast cancer the tumours grew to three times the size of tumours in a control group of rats not receiving the drug. Horrobin said diazepam promoted tumours only at low doses - doses that were disturbingly close to those for humans.
Hoffman-La Roche, the world's largest manufacturer of diazepam, challenges the results of the study. The company's British research consultant Dr Francis Roe has described Horrobin's work as "inconclusive and trivial".
But doctors at the Canadian Health Protection Branch believe the claims are worth investigating. Dr Ian Henderson said: "We can't close our eyes and not investigate."
Dr Denys Cook, director of drug research at the branch, says there is no question of withdrawing diazepam "but withdrawal would remain an option during the course of the investigation should the research indicate evidence of a link".
FEDERAL GOVERNMENT TO TEST MONTREAL MD'S CLAIMS THAT DIAZEPAM IS A CANCER PROMOTOR - College of Family Physicians of Canada, 1981
OTTAWA - The federal government plans to test diazepam to see if it is a cancer promotor, as a Montreal researcher has charged.
Dr. David Horrobin presented his own and other researchers' evidence at the recent meeting of the American Association for the Advancement of Science that the drug may speed the spread of existing cancer or make tissues more sensitive to carcinogens. (See "Diazepam Said To Be a Tumour Promotor at Therapeutic Levels", CFP News, February 1981, pp. 192-194.)
At that time, he said that further in vitro and animal research into the possibility is "urgently required".
His remarks were met by a lengthy rebuttal from Dr. F. J. C. Roe, a British consultant to Hoffman-La Roche, manufacturers of Valium. Dr. Roe concluded that Dr. Horrobin's evidence is "inconclusive and trivial and in no way justifies the fuss that he is trying to create".
Since that time, the debate has continued in letters to the editors of The Lancet and New Scientist.
'Warrants Research Fairly Soon'
The Canadian government's health protection branch has followed Dr. Horrobin's work for several years, and now feels there is "enough discussion to warrant some kind of research, fairly soon", according to Dr. Denys Cook, director of the bureau of drug research at the health protection branch.
He told Canadian Family Physician last month that the controversy has been mounting since mid-1979, when the director of the Clinical Research Institute of Montreal said that Dr. Horrobin's study of diazepam's effect on transplantable mammary tumours in rats could not be repeated. (Dr. Horrobin has charged that he was fired from his post as director of the endocrine pathophysiology laboratory at the Institute by its director, Dr. Jacques Genest, because of an interview Dr. Horrobin gave to The Globe and Mail discussing his research and criticizing the Medical Research Council and National Cancer Institute of Canada for not funding his work or commissioning another laboratory to do it.)
If the work could not be repeated, it might indicate variability in diazepam's effect, differing interpretation of results or problems in experimental design, Dr. Cook suggested. However, he noted that Dr. Genest's doubts about the repeatability were contained only in a press release published in The Lancet. A full report of the repeated experiments has not appeared, he added.
Another aspect of Dr. Horrobin's work - his research with Dr. James Trosko, Michigan State University, on diazepam and known tumour promotors' blocking effect on metabolic cooperation between cells - is "plausible and intriguing", but "a long way from the human situation", Dr. Cook commented.
"Government scientists are currently planning their research design", he said. They may start with bacterial cells, moving on to cultured mammalian cells and then experimental animals with induced tumours. "I don't think we'll use the transplant method, but I won't rule it out", he commented.
"If we get answers early in the game that clear it or clinch it (diazepam's role as a cancer promotor), then we won't go any further", he added. "But I suspect it's not as simple as that".
The federal study, estimated to cost $150,000-$200,000, will last about a year, Dr. Cook said. Until government researchers find evidence of its harmful effects, there are no plans to withdraw diazepam from the market, he added.
In material sent to CFP, Dr. Horrobin pointed out further evidence that diazepam may be a risk factor for cancer development. Papers published in 1974 and 1978 were recently brought to his attention by a member of the Johns Hopkins Hospital pathology department. In a letter to The Lancet, he said one study showed that oxazepam, a major metabolite of diazepam in humans but not in rats, caused liver cell tumours in three of 28 mice given a "lower dose" and 13 of 28 mice given a "higher dose", Dr. Horrobin said. Yet none of the 28 controls developed such tumours, he added.
"The authors concluded, 'This paper constitutes the first report of irreversible liver damage and neoplasia associated with benzodiazepines, an area which warrants further study' ", Dr. Horrobin quoted.
VALIUM-CANCER CLAIMS GET A COOL RECEPTION - The Sydney Morning Herald, January 2, 1981 by Gregory Turnbull, Medical Reporter
A Canadian doctor's claim that the tranquilliser Valium may promote cancer growth has been greeted coolly by other overseas experts and the NSW State Cancer Council.
Dr David Horrobin, formerly of the Clinical Research Institute of Montreal, but now working in Britain, called in London yesterday for public warnings about the "potential risk" faced by users of diazepam, the active ingredient of Valium and several less well-known drugs.
He emphasised that he suspected that diazepam was a promotor of cancer, not a direct cancer-causing agent.
He said tests conducted by the Montreal institute had found that diazepam hastened the growth of tumours in rats. This was particularly worrying because diazepam was sometimes given to women suffering from breast cancer.
The director of the State Cancer Council, Dr Gordon Sarfaty, said he "would not advise anyone to react too strongly" to the claims.
Valium is a widely used and frequently abused prescription drug.
Like almost all drugs, it can sometimes produce adverse reactions, which according to the 1980 MIMS Australian pharmaceutical directory, include drowsiness, fatigue, hypotension, confusion, depression, constipation, headache, hiccups, jaundice, nausea, changes in libido, changes in salivation, urinary retention, skin rash, slurred speech, vertigo and blurred vision.
Roche Products, the manufacturer of Valium, asked in London if "cancer promotion" should be included on the list of possible adverse reactions of the drug, said that long-term, large-scale animal tests had cleared diazepam of cancer-causing or promoting effects.
In his Montreal experiments, Dr Horrobin transplanted breast tumours into rats which were then given doses of diazepam two to three times larger than the usual human dose.
After four weeks, the tumour weight was almost three times higher in the diazepam group than in a control group.
"None of the evidence to date is conclusive in demonstrating that diazepam can cause or accelerate cancer growth in humans." Dr Horrobin said in London.
"But the evidence is already substantially stronger than is the case with many substances which have been banned, or about which official warnings have been given."
Dr Sarfaty said yesterday that he knew of no evidence linking diazepam with cancer growth.
"I have not yet seen Dr Horrobin's work, but on the face of it, I would not advise anyone to react too strongly to it," Dr Sarfaty said.
"The public is exposed to reports of a lot of things which are said to cause cancers in experimental animals, many of which are found later to have no relevance to humans."
In London, a leading cancer specialist, Dr Francis Rose, said that Dr Horrobin's study was "not of a substantial nature," and provided no evidence of a cancer risk for humans.
Hypnotics' association with mortality or cancer, Kripke DF, Langer RD, Kline LE, BMJ Open, February 27, 2012.
The Dark Side of Sleeping Pills, Daniel F. Kripke, MD, Revised: February 2012. PDF File.
Sleeping pills increase risk of death, study suggests, The Guardian, February 27, 2012.
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