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Radon, mycotoxins, p53, and uranium mining
Radon, mycotoxins, p53, and uranium mining
May I widen the scope of this correspondence? Stroke is the disorder seen by UK neurologists after epilepsy, and headache, migraine. In my view a general physician with a specific interest in neurology would be equally competent to see such patients, so halting the ever-increasing work-load of neurologists. Yet the ABN and the Royal College of Physicians of London Neurological Committee both oppose most common
SIR-We were intrigued by the remarkable specificity and high frequency of AGG-ATG mutations in p53 at codon 249 (arg-+met) reported by Taylor and colleagues (Jan 8, p 66) in cancers from uranium miners exposed to high doses of radon. It is difficult to imagine that radon, which presumably exerts its mutagenic and carcinogenic effects by producing a-particles, and causes gross damage to DNA (eg, doublestrand breaks) would also produce such a precise change in DNA. Of chemical carcinogens, aflatoxin B1 provides the best example of mutagenic specificity in p53. In bacteria, activated aflatoxin B1 induces G- T transversions; in vitro aflatoxin Bl, specifically targets the third nucleotide of codon 249 (AGG) of the human p53 gene; a high frequency of mutations at this same "hot spot" occurs in hepatocellular carcinomas in people chronically exposed to aflatoxins.1 What mechanism might explain the high prevalence of codon-249 mutations in lung cancer in uranium mines? Sram et al2 recently reported that miners working in deep uranium mines in Czechoslovakia are exposed to chemical mutagens, in addition to radon daughter products. Moulds were found in throat swabs from 27% of 116 miners compared with 5% of 78 controls. Various mycotoxins, including sterigmatocystin, was present in throat swabs taken from miners. Sterigmatocystin is a bisfuranoid mycotoxin structurally related to, and a precursor of, aflatoxins. Like aflatoxin Bl, it is a potent carcinogen and mutagen and its metabolite, sterigmatocystin-1,2-epoxide, forms an adduct with Nof guanine with the same stereochemistry as the analogous 8,9-epoxide of aflatoxin Bl. Sterigmatocystin produces squamous carcinomas and adenocarcinomas of the lung in animals.3 Of 16 lung cancers reported by Taylor et al,’12 were squamous cell carcinomas. We suggest, therefore, that exposure of uranium miners to mycotoxins such as sterigmatocystin could account for the p53 mutations reported. Among 19 lung cancers from uranium miners in New Mexico, only 9 p53 mutations were found; none were G-to-T transversions.’’ Fungi thrive in moist conditions. Perhaps uranium mines in Colorado and Czechoslovakia are damper than those in New Mexico. Thus, it would be of great interest to survey uranium miners in Colorado for exposure to
lung
mycotoxins. Stanley Venitt, Patrick J Biggs Section of Molecular Carcinogenesis, Haddow Laboratories, Institute of Cancer Research: Royal Cancer Hospital, Sutton, Surrey SM2 5NG, UK
1 International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. Lyon: IARC 1993, 309-95. 2 Šrám RJ, Binkova B, Dobias L, et al. Monitoring genotoxic exposure in uranium miners. Environ Health Perspect 1993; 99: 303-05. 3 Gopalakrishnan S, Liu-X, Patel DJ. Solution structure of the covalent sterigmatocystin-DNA adduct. Biochemistry 1992; 31: 10790-801. 4 Vähäkangas KH, Samet JM, Metcalf RA, et al. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet 1992; 339: 576-80.
General
physicians and neurology
SiR-Joining
in the debate
whether patients with stroke neurologist, the Association of British Neurologists (ABN) (Feb 26, p 544) notes that there are about 200 whole-time consultant neurologists in the UK so that if neurologists were to see all strokes that would mean about 14 stroke patients each week.
need to
see
a
on
further appointments of "general physicians with a special interest in neurology". In doing so the Royal College disregards its other committees and associate bodies who readily accept the notion of special interests in cardiology, gastroenterology, endocrinology, and thoracic medicine, for
example. After the 1939-45
teaching hospitals and regional hospitals appointed physicians with an interest in neurology. I was one of them; having served as registrar and senior registrar to general physicians and to a consultant neurologist, I was appointed to the Swindon/Cirencester hospitals in that capacity. When I retired in 1985 our clinical area had increased in population from 95 000 to 250 000 and there had been one retirement and three other general physicians with special interests had been appointed. A discussion document produced at the request of the Royal College of Physicians Committee of Internal Medicine at its meeting on Jan 9, 1985, noted that some years earlier I had made an "impassioned appeal ... for the preservation of the general physician with an interest in neurology, a species of which [I] was one of the last surviving members". This matter was also raised by Hopkins,l who wrote in 1984 that professors of medicine favoured this concept despite the lack of support by the RCP Committee on Neurology. If no expansion in the number of whole-time neurologists in the UK is planned I submit that physicians who have been trained in both general medicine and neurology as senior registrars or lecturers should be considered for appointment as consultant physician with an interest in neurology in regional hospitals where whole-time neurologist cover is not available. I had an excellent liaison for 30 years with neurological and neurosurgical colleagues and there was access to electroencephalography, neuroradiology, neuropathology, and neurophysiology before many of these were available on the hospital campus. My proposal might also help to resolve the plight of excellently trained and experienced senior registrars who, as they approach middle age, abandon hope of full recognition and employment. war some
Anthony G Freeman Meadow Rise, 3 Lakeside, Swindon, Wiltshire SN3
1
1QE, UK
Hopkins A. Different types of neurology. BMJ 1984; 288:
1733-36.
Thalidomide revisited SiR-While one can only endorse Jakeman and Smith’s conclusion that a "thalidomide analogue with less teratogenic potential" would "greatly benefit the world of leprosy", the rest of their commentary (Feb 19, p 432) exhibits a frightening
naivety. They
state that the World Health Organization has given "clear guidance" on the use of the drug and have made it clear that "the only female patients who should be exposed to the drug are those who are postmenopausal". Our television documentary Thalidomide: the drug that came back, shown in the UK last June, revealed that the use of thalidomide in Brazil’s leprosy programme, whose national coordinator assured us that the drug was never given to women of childbearing age, had led to at least 21 children being born damaged since the original use of the drug as a hypnotic was ended in the early
795
May I widen the scope of this correspondence? Stroke is the disorder seen by UK neurologists after epilepsy, and headache, migraine. In my view a general physician with a specific interest in neurology would be equally competent to see such patients, so halting the ever-increasing work-load of neurologists. Yet the ABN and the Royal College of Physicians of London Neurological Committee both oppose most common
SIR-We were intrigued by the remarkable specificity and high frequency of AGG-ATG mutations in p53 at codon 249 (arg-+met) reported by Taylor and colleagues (Jan 8, p 66) in cancers from uranium miners exposed to high doses of radon. It is difficult to imagine that radon, which presumably exerts its mutagenic and carcinogenic effects by producing a-particles, and causes gross damage to DNA (eg, doublestrand breaks) would also produce such a precise change in DNA. Of chemical carcinogens, aflatoxin B1 provides the best example of mutagenic specificity in p53. In bacteria, activated aflatoxin B1 induces G- T transversions; in vitro aflatoxin Bl, specifically targets the third nucleotide of codon 249 (AGG) of the human p53 gene; a high frequency of mutations at this same "hot spot" occurs in hepatocellular carcinomas in people chronically exposed to aflatoxins.1 What mechanism might explain the high prevalence of codon-249 mutations in lung cancer in uranium mines? Sram et al2 recently reported that miners working in deep uranium mines in Czechoslovakia are exposed to chemical mutagens, in addition to radon daughter products. Moulds were found in throat swabs from 27% of 116 miners compared with 5% of 78 controls. Various mycotoxins, including sterigmatocystin, was present in throat swabs taken from miners. Sterigmatocystin is a bisfuranoid mycotoxin structurally related to, and a precursor of, aflatoxins. Like aflatoxin Bl, it is a potent carcinogen and mutagen and its metabolite, sterigmatocystin-1,2-epoxide, forms an adduct with Nof guanine with the same stereochemistry as the analogous 8,9-epoxide of aflatoxin Bl. Sterigmatocystin produces squamous carcinomas and adenocarcinomas of the lung in animals.3 Of 16 lung cancers reported by Taylor et al,’12 were squamous cell carcinomas. We suggest, therefore, that exposure of uranium miners to mycotoxins such as sterigmatocystin could account for the p53 mutations reported. Among 19 lung cancers from uranium miners in New Mexico, only 9 p53 mutations were found; none were G-to-T transversions.’’ Fungi thrive in moist conditions. Perhaps uranium mines in Colorado and Czechoslovakia are damper than those in New Mexico. Thus, it would be of great interest to survey uranium miners in Colorado for exposure to
lung
mycotoxins. Stanley Venitt, Patrick J Biggs Section of Molecular Carcinogenesis, Haddow Laboratories, Institute of Cancer Research: Royal Cancer Hospital, Sutton, Surrey SM2 5NG, UK
1 International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. Lyon: IARC 1993, 309-95. 2 Šrám RJ, Binkova B, Dobias L, et al. Monitoring genotoxic exposure in uranium miners. Environ Health Perspect 1993; 99: 303-05. 3 Gopalakrishnan S, Liu-X, Patel DJ. Solution structure of the covalent sterigmatocystin-DNA adduct. Biochemistry 1992; 31: 10790-801. 4 Vähäkangas KH, Samet JM, Metcalf RA, et al. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet 1992; 339: 576-80.
General
physicians and neurology
SiR-Joining
in the debate
whether patients with stroke neurologist, the Association of British Neurologists (ABN) (Feb 26, p 544) notes that there are about 200 whole-time consultant neurologists in the UK so that if neurologists were to see all strokes that would mean about 14 stroke patients each week.
need to
see
a
on
further appointments of "general physicians with a special interest in neurology". In doing so the Royal College disregards its other committees and associate bodies who readily accept the notion of special interests in cardiology, gastroenterology, endocrinology, and thoracic medicine, for
example. After the 1939-45
teaching hospitals and regional hospitals appointed physicians with an interest in neurology. I was one of them; having served as registrar and senior registrar to general physicians and to a consultant neurologist, I was appointed to the Swindon/Cirencester hospitals in that capacity. When I retired in 1985 our clinical area had increased in population from 95 000 to 250 000 and there had been one retirement and three other general physicians with special interests had been appointed. A discussion document produced at the request of the Royal College of Physicians Committee of Internal Medicine at its meeting on Jan 9, 1985, noted that some years earlier I had made an "impassioned appeal ... for the preservation of the general physician with an interest in neurology, a species of which [I] was one of the last surviving members". This matter was also raised by Hopkins,l who wrote in 1984 that professors of medicine favoured this concept despite the lack of support by the RCP Committee on Neurology. If no expansion in the number of whole-time neurologists in the UK is planned I submit that physicians who have been trained in both general medicine and neurology as senior registrars or lecturers should be considered for appointment as consultant physician with an interest in neurology in regional hospitals where whole-time neurologist cover is not available. I had an excellent liaison for 30 years with neurological and neurosurgical colleagues and there was access to electroencephalography, neuroradiology, neuropathology, and neurophysiology before many of these were available on the hospital campus. My proposal might also help to resolve the plight of excellently trained and experienced senior registrars who, as they approach middle age, abandon hope of full recognition and employment. war some
Anthony G Freeman Meadow Rise, 3 Lakeside, Swindon, Wiltshire SN3
1
1QE, UK
Hopkins A. Different types of neurology. BMJ 1984; 288:
1733-36.
Thalidomide revisited SiR-While one can only endorse Jakeman and Smith’s conclusion that a "thalidomide analogue with less teratogenic potential" would "greatly benefit the world of leprosy", the rest of their commentary (Feb 19, p 432) exhibits a frightening
naivety. They
state that the World Health Organization has given "clear guidance" on the use of the drug and have made it clear that "the only female patients who should be exposed to the drug are those who are postmenopausal". Our television documentary Thalidomide: the drug that came back, shown in the UK last June, revealed that the use of thalidomide in Brazil’s leprosy programme, whose national coordinator assured us that the drug was never given to women of childbearing age, had led to at least 21 children being born damaged since the original use of the drug as a hypnotic was ended in the early
795