I welcome the publication of recent papers by Cherry and her
collaborators.[1] [2] Although they form part of a large number of
epidemiological studies, referenced by the authors, based solely on
questionnaire data they do add significantly to the understanding of the
ill-health of Gulf War Veterans (GWVs). The limitations of such studies
are recognised by the authors, for example, the lack of any bas...
I welcome the publication of recent papers by Cherry and her
collaborators.[1] [2] Although they form part of a large number of
epidemiological studies, referenced by the authors, based solely on
questionnaire data they do add significantly to the understanding of the
ill-health of Gulf War Veterans (GWVs). The limitations of such studies
are recognised by the authors, for example, the lack of any baseline
information prior to the Gulf war, the lack of any exposure data for the
period spent in the Gulf, and the absence of many records.
Once again there has been found an excess of the numbers and severity
of symptoms amongst GWVs compared with a carefully chosen control group.
It has been shown that these important and disturbing findings cannot be
attributed to either excessive smoking or drinking amongst the veterans.
The analysis of the data also clearly shows that the GWVs are reliable and
accurate in their recall of information even in the extensive absence of
official records. The abject failure in record keeping/preservation by the
Ministry of Defence is again identified. However, 10 years after the Gulf
War it is cause for considerable concern that only very limited clinical
studies of the health of GWVs have been reported in the UK.
The first major finding identifies an association of severity of
symptoms with pesticide handling in a manner that suggests a causal
connection with peripheral neuropathies. This is new and accords with
individual eyewitness accounts from the field[3] and some longstanding
clinical studies. The second major finding confirms the
association of symptoms and severity with the numbers of vaccines
administered. It does not support the contentious and highly
criticised,[4] and subsequently modified,[5] claim that only vaccines given in
theatre were associated with excessive symptoms and severity.
The case made by the authors would have been considerably
strengthened if they had recognised important clinical studies and
investigations already carried out on some GWVs both in this country and
the USA. Jamal et al have reported a small clinical
study on UK veterans that identified peripheral neuropathy similar to that
found in organophosphate-poisoned farmers.[6] [7] Mackness and coworkers
have found, across all genotypes, a reduction of approximately 50% in the blood levels
of PON 1, an enzyme with a key role in the metabolism organophosphate
pesticides.[8] PON 1 plays an important protective role in the
cardiovascular system[9] and in the aetiology of diabetes related
damage.[10] In the United States Haley, whose epidemiology has been much
criticised,[11][12][13] identified three major syndromes[14] [15] two of
which, confusion-ataxia and arthro-myo-neuropathy, were associated with
adverse reactions to NAPS tablets (pyridostigmine bromide). Arthro-myo-neuropathy syndrome was also strongly associated with the (excessive) use of the
insect repellent DEET. Impaired cognition was associated with the wearing
of flea collars. All these exposures feature prominently in the analysis
carried out by Cherry and her co-workers.[1] [2] Crucially, after his
epidemiological survey, Haley investigated the sick veterans clinically.
He identified extensive and 'generalised injury to the central,
peripheral, and autonomic nervous systems.'[16] More recent papers have
shown both functional and structural deficits in the central nervous
system including the left basal ganglia, and brain stem.[17] [18] This
accords with the 'poor functioning of the central nervous system'
associated by Cherry et al with their neurological
factor which was not dissected further to explore only central nervous
system effects. Haley has also shown significant variations in PON1 enzyme
levels, which varied with the genotype.[19] Abou-Donia has shown, in
animal studies, that there is synergism between insecticides of different
classes, organophosphates and pyrethrins, which is exacerbated with
DEET.[20] He has found specific antibodies to neuronal markers in one boy
exposed to chlorpyrifos,[21] the major organophosphate used by the
Americans in the Gulf. Despite the initial and vehement denial of the use
of organophosphates by UK forces it emerged that these had been used extensively,[22]
and with very little control.[3] [23] Furthermore the trained operatives
were not supplied with effective protective clothing to carry out spraying
and dusting with these insecticides.[3] [23]
Although UK authorities have strenuously denied any exposure to nerve
agents and other chemical warfare agents,[24] it is clear that the
Americans now recognise that a substantial number of their troops were
exposed to low levels of nerve agents which produced only transient and in
some cases no immediate symptoms.[17] [23] [26] Eye witness accounts
support this view.[3] [26][27]
The 'cholinergic triple whammy' of NAPS, organophosphate
insecticides, and nerve agents would be expected to exert severe and
extensive effects on the central, peripheral, and autonomic nervous
system. The use of NAPS has been heavily criticised,[28] and is consistent
with the high incidence of side effects reported: approximately 50% in the
army.[2]
Recently a tilt table study of the widespread loss of cardiovascular autonomic control among veterans has been announced in the United
States.[29] Baumzweiger includes assessment of orthostatic hypotension in
his examination and treatment of sick veterans in the United States.[30]
All this evidence provides very convincing support for a causal
relationship between exposure to NAPS, pesticides, and DEET in the health
of the GWVs. The study provides very strong evidence for the reliability
and accuracy of the responses by GWVs even in the absence of records-over
all only 27.5% of GWVs have any vaccination records.
Although the Ministry of Defence has insisted that no more than 10
different vaccines were given to the veterans[24] [28] it is noteworthy
that 11% reported receiving 10 or more vaccines. The association of ill
health with numbers of vaccines administered is consistent with other
studies.[31] What is lacking, along with most of the records, is the time
frame for these inoculations. Adverse effects are well known when too many
vaccines are administered too close together. The theoretical proposal of
Rook and Zumla[32] concerning a possibly severe disturbance of the Th1/Th2
ratios is referred to, but not the work of Nicolson[33][34] and
Vodjani[35] who have found mycoplasma species, particularly M fermentans
incognitus, in about half of American veterans examined. These are also
present in other chronic illnesses, myalgic encephalomyelitis, ME,
fibromyalgia, and rheumatoid arthritis where a compromised immune system
is thought to play an important role in the pathology. Repeat cycles of
powerful antibiotics, with appropriate support for the gut, have proved an
effective therapy in some of these cases.[36] A major study is presently
under way in the States with doxycycline and ciprofloxacin.[37]
An important aspect of the widespread exposure to many and varied
toxins in the Gulf is the question of synergy. Can the important data base
assembled by these investigators be used to explore this question? Synergy
is known for pesticide exposure.[20] The well documented effects of organophosphates on
the immune system in man,[38] which were deliberately ignored by the COTS
Committee,[39] provide a further example of possible synergistic or at
least additive adverse effects. The immune system has suffered from more
than the obvious exposure to vaccines.
Exposure to oil and smoke was consistently identified with severity
(the best indicator) of symptoms but dropped from further consideration of
the respiratory factor after allowing for other exposures. It is not clear
what these factors are, but NAPS and organophosphates and vaccines are all known to
exert profound effects on the respiratory system and would be expected to
exert synergistic or additive adverse effects. Adverse effects from
exposure to oil and smoke have been reported and would be
expected,[40][41][42][43] although official publications deny any such
possibilities.[44]
Although the authors report a study drawing attention to the
importance of gastrointestinal symptoms[45] they do not emphasise the
association with such symptoms in their own study. Table 6 in Part I shows
that the gastrointestinal factor is significant in all veterans ranging
from the essentially well (cluster 2) to the most severely affected
(cluster 6). Our own preliminary studies have identified the importance of
gastrointestinal dysfunction as a major factor, in a small sample of GWVS,
which responds to dietary changes.[46]
The arbitrary division of exposures into three factors includes,
'factors reflecting individual susceptibilities'.[2] These encompass 'felt
that life was in danger', sought medical attention in Gulf, and
experienced side effects from NAPS. A much greater factor in personal
susceptibilities is the biochemistry of the individual and his or her
capacity for handling external chemical and biological toxic insults. The
importance of the varied and extensive cytochrome P-450 enzymes confer
remarkable variations in susceptibility to xenobiotics.[47] The
association of genetic halotypes with some major chronic autoimmune
diseases is well known.[48] This susceptibility could well lead to a range
of vaccine induced illnesses. However the conflicting data on PON 1
levels[3][19] illustrates the urgent need for further studies of all these
important issues.
The very low reporting of possible exposure to depleted uranium (DU)
was understandable at the time the questionnaires were completed. However,
recent events, including leaks of official military documents and
memos,[24] [49][50] as well as the identification of DU in the urine of
GWVs,[51] and people living in Yugoslavia,[52] indicate widespread
exposure has occurred in areas where DU munitions have been used. An
independent report commissioned by the American veterans surveyed 10 000
veterans and found the 75-80% had been in areas where they could have been
exposed to DU.[53] [54]
The data and analysis presented in these papers is consistent with
the thesis that the exposure of GWVs to an excessive load of many and
varied chemical and biological toxins is responsible for the adverse
health effects they are now suffering.[6][7] [14][15][16][17] [28] [54]
M Hooper
School Sciences
University of Sunderland
UK
1. Cherry N, Creed F, Silman A, et al. Health and exposures of United Kingdom Gulf war veterans. Pt I: the pattern and extent of ill health. Occup Environ Med 2001;58:291-8.
2. Cherry N, Creed F, Silman A, et al. Health and exposures of United
Kingdom Gulf war veterans. Pt II: The relation of health to exposure.
Occup Environ Med 2001;58:299-306.
3. Worthington AJ. Information supplied to House of Commons Defence
Committee, 1994-6. Testimony of Sgt. Worthington AJ, Environmental
Health Technician on use of Pesticides. Commendation by Lt. Colonel BK
Reece-Russell.
4 Hotopf A, David A, Hull L, et al. Role of vaccinations as risk factors
for ill health in veterans of the Gulf war: cross sectional study. BMJ 2000;320:1363-7.
5 Electronic Letters by several authors in response to Hotopf paper
available at bmj.com eLetters for Hotopf et al. BMJ 2000;320:1363-7.
6 Jamal GA, Hansen S, Apartopoulos F, et al. The 'Gulf War syndrome'. Is
there evidence of dysfunction in the nervous system? J Neurol Neurosurg Psychiatry 1996;60:449-50.
7. Jamal, GA. Gulf War Syndrome-a model for the complexity of biological
and environmental interaction with human health. Adverse Drug React Toxicol Rev 1998;17:1-17.
8. Mackness B, Durrington PN, Mackness MI. Low paraoxonase in Persian Gulf
War veterans self-reporting Gulf War Syndrome. Biochem Biophys Res Comm 2000;276:729-33.
9. Mackness B, Hunt R, Durrington PN, et al. Increased immunolocalization
of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall
with the progression of atherosclerosis. Arterosclerosis thrombosis and
Vascular Biology 1997;17:1233-8.
10. Mackness B, Mackness MI, Arrol S, et al. Serum paraoxonase (PON1) 55
and 192 polymorphism and paraoxonase activity and concentration in non-
insulin dependent diabetes mellitus. Atherosclerosis 1998;139:341-9.
11. Wadman M. US panel draws blank on Gulf War symptoms. Nature
2000;407:121.
12. Wadman M. Fracas over $5 million Gulf syndrome grant. Nature
2001;410:135.
13. Haley RW. Gulf syndrome research has passed peer review. Nature
2001;410:739.
14. Haley RW, Kurt TL. Self-reported exposure to neurotoxic chemical
Combinations in the gulf War: A Cross-sectional Epidemiologic Study. JAMA
1997;277:231-7.
15. Haley RW, Thomas LK, Horn J. Is there a Gulf War Syndrome: searching
for syndromes by factor analysis of symptoms. JAMA 1997;277:215-22.
16. Haley RW, Horn J, Roland PS, et al. Evaluation of neurologic function
in Gulf War Veterans. JAMA 1997;277:223-30.
17. Haley RW, Fleckenstein JL, Marshall WW, et al. Effect of basal ganglia injury on central dopamine activity in Gulf War Syndrome. Arch Neurol
2000;57:1280-3.
18. Roland PS, Haley RW, Yellin W, et al. Vestibular dysfunction in Gulf
War Syndrome. Otolaryngol Head Neck Surg 2000;122:319-30.
19. Haley RW, Billecke S, La Du BN. Association of low PON1 Type Q (Type A)
arylesterase activity with neurologic symptom complexes in Gulf War
Veterans. Toxicol Appl Pharmacol 1999;157:227-33.
20. Abou-Donia MB, Wilmarth KR, Jensen KF, et al. Neurotoxicity Resulting from coexposure to pyridostigmine bromide, DEET, and permethrin: implications of Gulf War chemical exposures. J Toxicol Environ Health 1996;48:35-56.
21. Abou-donia MB, Garretson LK. Detection of neurofilament autoantibodies
in human serum following induced neurologic disorder; a case report.
Environmental Epidemiology and Toxicology 2000;2:37-41.
22. Further memorandum concerning the provision of advice to MOD Ministers between 1994 and 1996 on the subject of organophosphate pesticide use during the Gulf War. London: Ministry of Defence, October 1997.
23. Studham C. Information supplied by OP Information Network, Elizabeth Sigmund, to House of Commons Defence Committee, 1994-6. Testimony of a paramedic on use of malathion.
24. http://www.mod.uk/policy/gulfwar/index.htm.
25. Sarin. In: Gulf War and Health Fulco EF, Liverman CT, Sox HC (eds). Institute of Medicine, National Academy Press, 2000;1:5-22.
26. 2nd Report by the Committee on Government Reform and Oversight,
Chairman Burton D. Union Calendar No. 228. 105th Congress, 1st Session
House Report 105-338, November 1997.
27. Thomas W. Bringing the War Home. Anchorage: Earthpulse Press,
1998.
28. Hooper M. The Most Toxic War in Western Military History. Evidence
submitted to the House of Commons Select Defence Committee, December 1999.
Published in 7th Report of Defence Select Committee. Gulf Veterans'
Illnesses. Report and proceedings of the Committee with Minutes of
Evidence and Appendices, April 19th 2000.
29. Gulf War Study, John Hopkins University details at
http://www.med.jhu.edu/gws/
30. Baumzweiger, W. Brainstem-Limbic Immune Dysregulation in 111 Gulf War
Veterans: A Clinical Evaluation of its Etiology, Diagnosis and Response to
Headache. International Journal of Medicine 1998;1:129-43.
31. Unwin C, Blatchley N, Coker W, et al. Health of UK servicemen who
served in the Persian Gulf War. Lancet 1999;353,:169-78.
32. Rook G, Zumla A. Gulf War Syndrome: is it due to a systemic shift in
cytokine balance towards a Th2 Profile? Lancet 1997;349:1831-3.
33. Nicolson GL, Nicolson, NL, Nasralla M. Mycoplasmal Infections and
Fibromyalgia/Chronic Fatigue Illness (Gulf War Illness) Associated with
Deployment to Operation Desert Storm. International Journal of Medicine
1997;1:80-92.
34. Nicolson GL. Chronic Infections as a Common Aetiology for many Patients
with Chronic Fatigue Syndrome, Fibromyalgia Syndrome and Gulf War
Illnesses. International Journal Medicine 1997;1:42-6.
35. Vojdani A, Franco AL. Multiplex PCR for the Detection of Mycoplasma
fermentans, M. Hominis and M. penetrans in Patients with Chronic Fatigue
Syndrome, Fibromyalgia, Rheumatoid Athritis, and Gulf War Syndrome.
1999;5:187-97.
36. Nicolson GL, Nasralla MY, Haier J, et al. Mycoplasmal Infections in
Chronic Illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War
Illness, HIV-AIDS and Rheumatoid Arthritis. Medical Sentinel 1999;4:172-6.
37. Operations Manual Veterans Administration Cooperative Study #475
Antibiotic Treatment of Gulf War Veterans' Illnesses.
38. Repetto R, Baglia S. Pesticides and the Immune system: The Public
Health Risks London: Earthscan Publications, 1996.
39. COTS Report. Organophosphates. Committee on the Toxicity of Chemicals
in food, Consumer Products and the Environment, Woods HF Chairman, Crown
copyright, 1999.
40. Petrucelli BP, Goldenbaum M, Scott B et al. Health effects of the 1991
Kuwait oil fires: a survey on the US Army troops. J Occup Environ Med 1999;41:433-9.
41. Stead CF. Oil Fires Petroleum and Gulf War Illness. Testimony to House
SubCommmittee on Human Resources and Intergovernmental Relations, Chairman
Shays C. June 26 1997. Stead CF. see also,
http://www.ngwrc.org/OilSmoke/kuwait oil fire information.htm.
42. Testimony to the Presidential Advisory Committee on Gulf War Veterans
Illnesses, March 26 1996.
43. Van Steenis D Incineration, Co-incineration and Health Memorandum to
the House of Lords, Hansard 27 July 1999.
44. Gulf War Veterans' Illnesses: VA, DOD Continue to Resist Strong Evidence
Linking Toxic Causes to Chronic Health Effects, in reference 26. See also
http://www.gulflink.osd.mil?owf_ii/ the official Pentagon web
site.
45. Ishoy T, Suadicani P, Guldanger B, et al. Risk factors for
gastrointestinal symptoms. the Danish Gulf war study. Dan Med Bull 1999;46:420-3.
46. Hooper M. Guts, Brains and Gulf War Veterans. Conference Proceedings of
Autism: Perspectives on Progress. Durham 5-7 April 2000. Sunderland:
Autism Research Unit, University of Sunderland, UK, 2000.
47. Bland JS, Costarella L,
Levin B, et al. Clinical Nutrition: A Functional Approach. Washington USA: The Institute for Functional Medicine, Gig Harbor, 1999:255ff.
48. Kuby J Immunology. 3rd Ed, New York: Freeman, 1997.
49. Memorandum for Headquarters, US Army Chemical School, 16 August 1993.
This is just one example of several leaked documents. some now appear at
the the web site in reference 24 above.
50. Fahey D. Case Narrative: Depleted Uranium (DU) Exposures, 1998.
Available at National Gulf War Resource Center, Inc. 1224 M St, NW
Washington, DC 20005, USA. http://www.gulfweb.org/ngwrc.
51. Durakoviæ A, Dietz KA, Horan P. Quantitative analysis of uranium
isotopes in Canadian, US, and British Gulf War Veterans. Eur J Nucl Med 2000;27:5-75.
52. Civilians Contaminated by Depleted Uranium BBC 2 Scotland, Thursday 12
April 2001 19.30. Transcript
http://www.bbc.co.uk/scotland/alba/programan/eorpa/transcripteng.shtml.
53. http://www.gulfweb.org/ngwrc.
54. Durakoviae A. On Depleted Uranium: Gulf War and Balkan Syndrome. Croatian Medical Journal 2001;42:130-4.
It has been clear for years, based on much published research, that
symptoms in office workers are associated with a number of environmental
factors in office buildings and also, independently, with psychosocial
stressors at work. So we were surprised to see a recent article by Marmot
et al. (1) report that, in offices in the Whitehall II Study, “raised
symptom levels appear to be largely due to a...
It has been clear for years, based on much published research, that
symptoms in office workers are associated with a number of environmental
factors in office buildings and also, independently, with psychosocial
stressors at work. So we were surprised to see a recent article by Marmot
et al. (1) report that, in offices in the Whitehall II Study, “raised
symptom levels appear to be largely due to a working environment
characterized by poor psychosocial conditions”(p. 288). The article
concluded that the physical environment in the offices had a small and
unimportant influence on these symptoms. The analyses, however, had
substantial limitations that were not mentioned. Furthermore, the
conclusions were inconsistent with much of the current scientific
literature, but the discussion cited only other studies that agreed with
the findings and none of the substantial literature that disagreed. We
expand on these points below.
1) Key environmental measurements and interpretations used by Marmot
et al. (1) in the 1991-1993 data collection are no longer considered
relevant by most indoor environmental scientists. Single metrics of total
volatile organic compounds that lump all compounds together have long been
considered inappropriate for predicting human response, because irritancy
and odor vary among specific volatile organic compounds by orders of
magnitude (2). Metrics based on counts of culturable airborne fungi and
bacteria do not detect most indoor microbial matter and “provide little
information about the microbial status of an indoor environment” (3)(p.
58). Also, many of the thresholds for acceptability used by Marmot et al.
are not considered relevant for studying building-related symptoms: e.g.,
dry bulb temperature between 19-24°C; carbon dioxide (CO2) ≤500
parts per million (ppm); or any particular number for total airborne fungi
or bacteria or volatile organic compounds. In addition, the lumping
together of extreme high and low levels for many of the parameters (e.g.,
combining very hot and very cold temperatures in one category and
comparing to a broad middle range of temperatures) is inappropriate –
high and low temperature (or high and low humidity) may have quite
different, even opposite, effects. Researchers using more current or
precise metrics have reported consistent associations between building-
related symptoms in office workers and both lower ventilation rates (6, 7)
and temperatures (8, 9). There is also a substantial literature showing
that visible dampness and mold, but not traditional airborne mold counts,
are consistently associated with asthma exacerbation and respiratory
symptoms in building occupants (3, 4).
2) The authors do not report the association of passive tobacco smoke
exposure at work with symptoms, although it is included in their models as
a confounding factor (1) and was strongly correlated with increased
symptoms (p = 0.004) in prior analyses of their data (5). The current
article does not consider passive tobacco smoke exposure to be an indoor
environmental risk factor, although it reports risk estimates for other
indoor air pollutants (1).
3) The paper cites prior studies that agreed with its findings, but
is inexplicably silent about the many prior studies that have disagreed
(1). Ventilation rate (6, 7) and temperature (8, 9), both objectively
assessed indoor environmental risk factors, have been significantly and
independently associated with symptoms in multiple prior office studies.
A 1999 review of studies reported between 1986 and 1999 found that (a) in
16 studies using measured ventilation rates, 20 of 27 comparisons of
different ventilation rates found increased symptoms associated with lower
measured office ventilation rates, and (b) 9 of 18 studies using CO2
measurements as simpler but less accurate indicators of ventilation rate
also found such associations (10). Nine articles on associations between
temperature and symptoms in offices, published between 1989 and 2004, show
overall that symptom prevalence increased systematically as temperatures
increased between about 21 and 24.5 ºC, almost entirely within the
“acceptable” reference level used in Marmot et all (1, 11).
We suggest further analyses of the Whitehall II data by Marmot et al.
to refine their findings and help resolve discordant results: a) the use
of environmental metrics based on current knowledge that symptoms in
office workers generally increase as temperatures increase above 21 or 22
ºC, as indoor CO2 increases above about 600 to 800 ppm, with presence of
passive tobacco smoke, and in buildings with air-conditioning or
humidification; b) statistical adjustment for season of study; c) the
inclusion of the additional psychosocial variables available in Whitehall
II (5); and d) separate analyses for outcomes of biologically related
symptom subgroups – rather than continuing to use the very nonspecific
“sick building syndrome” metric (for instance, lumps rash/itch together
with cold/flu) which may be sensitive to stress-related over-reporting but
insensitive to specific biologic effects.
In conclusion, substantial evidence suggests that psychosocial and
physical factors in indoor environments, as well as biological and
chemical factors, all influence the symptoms experienced by office
workers, through multiple mechanisms that we still do not understand.
Dismissing the importance of any of these indoor environmental risk
factors is not useful or, based on all that we know, justified.
Ultimately, researchers in many disciplines will be needed to help us
understand causation and prevention of this problem.
Mark J. Mendell and William J. Fisk,
Indoor Environment Department,
Lawrence Berkeley National Laboratory
Competing interests: none.
References
1. Marmot AF, Eley J, Stafford M, Stansfeld SA, Warwick E, Marmot MG.
Building health: an epidemiological study of "sick building syndrome" in
the Whitehall II study. Occup Environ Med 2006;63:283-289.
2. Molhave L, Clausen G, Berglund B, et al. Total Volatile Organic
Compounds (TVOC) in Indoor Air Quality Investigations. Indoor Air
1997;7:225-240.
3. Institute of Medicine Committee on Damp Indoor Spaces and Health. Damp
Indoor Spaces and Health. Washington, D.C.: National Academies Press,
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4. Park JH, Schleiff PL, Attfield MD, Cox-Ganser JM, Kreiss K. Building-
related respiratory symptoms can be predicted with semi-quantitative
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5. Marmot AF, Eley J, Nguyen M, Warwick E, Marmot MG. Building health in
Whitehall: An epidemiological study of causes of SBS in 6,831 civil
servants. In: Woods JE, Grimsrud DT, Boschi N, eds. Proceedings of Healthy
Buildings/ IAQ '97. Washington, DC, 1997:483-488.
6. Stenberg B, Eriksson N, Hoog J, Sundell J, Wall S. The Sick Building
Syndrome (SBS) in office workers. A case-referent study of personal,
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1994;23:1190-7.
7. Jaakkola JJ, Miettinen P. Ventilation rate in office buildings and sick
building syndrome. Occup Environ Med 1995;52:709-14.
8. Mendell MJ, Fisk WJ, Petersen MR, et al. Indoor particles and symptoms
among office workers: results from a double-blind cross-over study.
Epidemiology 2002;13:296-304.
9. Jaakkola JJ, Heinonen OP. Sick building syndrome, sensation of dryness
and thermal comfort in relation to room temperature in an office building:
Need for individual control of temperature. Environment International
1989;15:163-168.
10. Seppanen O, Fisk WJ, Mendell MJ. Association of ventilation rates and
CO2 concentrations with health and other responses in commercial and
institutional buildings. Indoor Air 1999;9:226-252.
11. Seppanen O, Fisk WJ. Some quantitative relations between indoor
environmental quality and work performance or health. ASHRAE Research
Journal 2006;(in press).
with regard to the limit of detection and to the data in table 5 and
figure 5, the level of benzene in blood has given in µg/l. I believe that
the correct indication should be in ng/l. As matter of fact, with a
personal exposure to benzene of 9.3-3.8 µg/m3, it is impossible to have a
blood benzene level of 213-195 µg/l which should be corresponding to an
environmental exposure to benzene of more than...
with regard to the limit of detection and to the data in table 5 and
figure 5, the level of benzene in blood has given in µg/l. I believe that
the correct indication should be in ng/l. As matter of fact, with a
personal exposure to benzene of 9.3-3.8 µg/m3, it is impossible to have a
blood benzene level of 213-195 µg/l which should be corresponding to an
environmental exposure to benzene of more than 20 ppm (65 mg/m3).
Francesco Brugnone
Thank you for the great editorial. I would like to suggest that
given your experience, especially Dr. Hoppin, it would be especially
helpful to formulate more specific proposals for introducing at the state
level, including California. The University of California, as an example,
has been largely unresponsive to requests for disclosures regarding
potential conflict of interest situations for facu...
Thank you for the great editorial. I would like to suggest that
given your experience, especially Dr. Hoppin, it would be especially
helpful to formulate more specific proposals for introducing at the state
level, including California. The University of California, as an example,
has been largely unresponsive to requests for disclosures regarding
potential conflict of interest situations for faculty, departments, and
research institutes. Circulating a proposal for endorsement by one or
more scientific societies might also foster a larger discussion of this
issue.
Thanks again for your good works.
Bruce H. Jennings, Ph.D.
Senate Environmental Quality Committee
State Capitol, room 2205
Sacramento, CA 95814
916.651.4108
Meredith et al,[1] performed a case referent study to investigate
asthma caused by isocyanates. They claimed that the results indicated that
isocyanate asthma occurs at low 8h average exposure (around 1.5 ppb); for
exposures above 1.125 ppb there was about a three fold increased risk,
however this was of limited statistical significance (OR=3.2, 95% CI 0.96-
10.6; p=0.06). They also concluded that their s...
Meredith et al,[1] performed a case referent study to investigate
asthma caused by isocyanates. They claimed that the results indicated that
isocyanate asthma occurs at low 8h average exposure (around 1.5 ppb); for
exposures above 1.125 ppb there was about a three fold increased risk,
however this was of limited statistical significance (OR=3.2, 95% CI 0.96-
10.6; p=0.06). They also concluded that their study, in contrast with
other studies, showed a higher risk of isocyanate asthma in smokers and
persons with atopy.
The study design is original as cases were recruited from a register
of occupational asthma cases. A case reference study based on a register
of cases with both the disease and the exposure of interest is new. I
think the design requires some discussion as it may introduce severe bias.
A typical case-referent study selects cases with a certain disease-
for example, asthma from a hospital register or in a population survey.[2] The referents should be selected in to give an unbiased estimate of
exposure frequency in the study base.[3] The study base of a register,
including occupational asthma cases, is the population that in the case of
having asthma would be reported to the register. Therefore, the authors of
this study matched the referents to the cases by reporting doctor and
factory/production area. Then they measured/estimated the exposure level
for both cases and referents and found that the average 8h exposure was
higher among cases. This design has certain weaknesses illustrated by the
following hypothetical situations:
1. Assume that the exposure in the production area is homogenous.
Then both cases and referents would have the same exposure and the
conclusion would be that the risk was independent of exposure level.
2. Assume that the reporting doctor only knows a proportion of
incident cases, a reasonable assumption. If seeing the doctor is dependent
on exposure level, a bias is obvious.
3. Assume that there was no increased risk at all in the workplaces
at the current exposure but that there was exposure to irritants, which
varied within the production area. Then cases with asthma would probably
be more likely to report problems with their asthma to the occupational
health physician. There would also be an association with all substances
whose concentration was correlated to the irritant.
4. Assume that there was no causal association between the exposure
and the occurrence of asthma at the current levels. As asthma is common
among persons with atopy, the study would certainly indicate that atopy
was a risk factor in combination with the exposure.
Some of these biases could be avoided if there was some specific test
that with certainty established the causal association between asthma and
the exposure among the cases. Asthma caused by isocyanates can with some
certainty be established by provocation, but the study by Meredith
included no routine provocation test.
If it is presumed that all the reported cases really are caused by
isocyanates, a rather improbable assumption according to the case
definition, the conclusion by the authors that isocyanate asthma occurs
also at very low exposures without any threshold could be made without
doing any case-referent analysis. They could just simply measure the
exposure of the cases and conclude that the lowest measured exposure
obviously caused isocyanate asthma. It is obviously impossible to
determine any other threshold.
Is there a proper design of a case-referent study based on cases
identified through a register where the association between exposure and
outcome is already established? If the disease is caused by short term
high exposure a case-crossover design seems possible.[3] However, that
design requires a very accurate determination of when the disease started,
which rarely is possible for asthma. Another possibility is to estimate
the study base from which the cases are recruited-for example, in the
study by Meredith et al[1] the number of person years in the different
production areas where the cases were detected should have been estimated.
This requires that all or most incident cases from that area is known or
there should at least not be any differential reporting of cases between
the areas.
Thus, the design of this study is interesting but includes many
possibly bias of which a just a few were discussed in the paper. The
conclusions that the risk of isocyanate asthma is increased at levels
around 125 ppb, and is more common among persons with atopy and smokers
are questionable.
Bengt Jarvholm,
Department of Public Health and Clinical Medicine
Umea University SE-901 85 Umea
Sweden
1. Meredith SK, Bugler J, Clark RL. Isocyanate exposure and
occupational asthma: a case referent study. Occup Environ Med 2000;57:830-
836.
2. Toren K, Jarvholm H, Hrisman J, et al. Adult onset asthma and
occupational exposures. Scand J Work Environ Health 1999;25:430-5
3. Rothman KJ, Greenland S. Modern Epidemiology. (2nd ed)
Philadelphia: Lippincott-Raven, 1998.
In their publication, the authors postulate that effects upon health
and
performance cannot be ruled out despite a low exposure to high-frequency
electro-magnetic fields, effects far below the WHO threshold values.
Unfortunately, this paper has substantial methodological problems.
1. There may well have been a clustering in the choice of test-
subjects’
addresses in relation to the location...
In their publication, the authors postulate that effects upon health
and
performance cannot be ruled out despite a low exposure to high-frequency
electro-magnetic fields, effects far below the WHO threshold values.
Unfortunately, this paper has substantial methodological problems.
1. There may well have been a clustering in the choice of test-
subjects’
addresses in relation to the location of the mobile phone base stations.
For
example, in the sense that other environmental influences may have
affected
everyone in the same cluster. In this case, the independence of the people
within the cluster may no longer be given, which in turn may lead to an
overestimation of the effective sample size, and therefore to progressive
(results are too often significant) decisions. In order to control this
effect, the
Intra-Class-Correlation should have been calculated to give an impression
of
the effective sample size. In the light of the few, tightly significant
results,
such effects may have played a decisive role.
2. It still remains unclear as to whether there are a priori
differences as to
the degree of “concerns about base station“ in relation to the
expositional
groups. This was unfortunately not presented in table 1. What was the
percentage of test-persons who were concerned, and to what extend? How is
this distributed throughout the groups? In addition, the degree of concern
was measured on a ranking-scale, despite the fact that the co-variance
analysis demands an interval scaled co-variant.
3. The Zerssen Scale was evaluated dichotomously, whereby even very
slight complaints (“1“) were already registered as complaints. This then
raises
the question as to whether the named effects in the Zerssen scale would
still
be evident if one had pooled the groups 0 and 1 (no, and/or light
complaints), and the complaints-group 2 and 3. Who doesn’t sometimes
suffer of headaches, dizziness, and appetite disorders, etc? It would be
interesting to see how the complaints - before a dichotomization – were
distributed amongst the exposition-groups.
4. In Table 2, 13(!) covariance analyses were carried out, from which
the p-value of one main effect reaches tendency level (p<0.1). After the
implementation of a Bonferroni-Holm-Correction, which strictly seen should
also include the p-values inside the covariance analyses, there are no
effects
to be found whatsoever. In this case, it is then not permitted to omit the
non-
significant co-variables, even in the co-variance analysis. The model for
the
covariance analysis must always be set, a priori, before testing;
otherwise a
Type I-error-inflation will ensue. The attained significance would only
then be
credible if confirmed on the basis of a further sample.
5. If one would adjust the p-values in table 4 according to the
Bonferroni-
or Bonferroni-Holm-convention, then none of the symptoms would be
significant anymore. The same would apply to the effects shown in table 5.
To sum up: A scientifically founded evaluation would have had to have
seen
corrections according to Bonferroni-Holm (or some other). Had this
happened, there would be no significant result, and thereby no provable
effects. Certain information was not included in the tables, such as the
nature
of the dichotomization and choice of sample. This creates the impression
that
hypothesis finding and hypothesis testing were not done quite
independently
of each other, or at least, that there is little in this study to revoke
this
impression. However, the results beg a prompt replication with all
details,
hypotheses, and corresponding evaluation criteria fixed a priorily.
We read with interest the report by Desrosiers et al of the
association between maternal occupational exposure to organic solvents and
some birth defects [1]. Their case-control study examined occupational
exposure to three classes of solvents (chlorinated, aromatic and Stoddard)
and found one association -- between neural tube defects (mainly spinal
bifida) and maternal occupational exposure to chlorinated solvents, but n...
We read with interest the report by Desrosiers et al of the
association between maternal occupational exposure to organic solvents and
some birth defects [1]. Their case-control study examined occupational
exposure to three classes of solvents (chlorinated, aromatic and Stoddard)
and found one association -- between neural tube defects (mainly spinal
bifida) and maternal occupational exposure to chlorinated solvents, but no
association with the other solvent classes or with oral clefts. In their
discussion, the authors noted that previous findings of maternal
occupational exposure to solvents and oral clefts were from European,
mainly French, populations and hypothesized that the inconsistency between
their results and these previous studies might be due to different
exposure profiles (e.g., intensity, solvent formulation). Although this
explanation is plausible, another must be discussed: differences in the
definition of exposure. Our research team conducted four of the five
studies with positive results cited by Desrosiers et al[2][3][4][5]. All
four were population based and included, in addition to the solvent
classes considered by Desrosiers et al, oxygenated solvents, for example
alcohols or glycol ethers. Exposure limited to only oxygenated solvents
appears to be very frequent among working women: more than half of the
solvent exposure group in Chevrier et al [4] were exposed only to that
solvent class. Because previous studies found the increased risk of oral
clefts to be associated principally with that specific exposure, the
failure to consider this association could explain the negative findings
for oral clefts. Moreover, women who were exposed only to oxygenated
solvents are included in the reference ('non-exposed') group here, which
would result in underestimating associations with chlorinated and
petroleum solvents. For both these reasons, we think that the failure to
consider oxygenated solvents led to underestimating the risk estimates for
oral clefts.
1. Desrosiers, T.A., et al., Maternal occupational exposure to
organic solvents during early pregnancy and risks of neural tube defects
and orofacial clefts. Occup Environ Med 2012;69:7 493-499 Published Online
First: 23 March 2012 doi:10.1136/oemed-2011-100245.
2. Cordier, S., et al., Maternal occupational exposure and congenital
malformations. Scand J Work Environ Health, 1992. 18(1): p. 11-7.
3. Lorente, C., et al., Maternal occupational risk factors for oral
clefts. Occupational Exposure and Congenital Malformation Working Group.
Scand J Work Environ Health, 2000. 26(2): p. 137-45.
4. Chevrier, C., et al., Occupational exposure to organic solvent mixtures
during pregnancy and the risk of non-syndromic oral clefts. Occup Environ
Med, 2006. 63(9): p. 617-23.
5. Garlantezec, R., et al., Maternal occupational exposure to solvents and
congenital malformations: a prospective study in the general population.
Occup Environ Med, 2009. 66(7): p. 456-63.
We thank Wolf and Vana for their comments on our article "Subjective
symptoms, sleeping problems and cognitive performance in subjects living
near mobile phone base-stations" (OEM 63:307-313). We appreciate their
regret that due to methodological problems results may not be as clear-cut
as they desire.
The study of potential effects of emissions from mobile phone base-
stations is indeed fr...
We thank Wolf and Vana for their comments on our article "Subjective
symptoms, sleeping problems and cognitive performance in subjects living
near mobile phone base-stations" (OEM 63:307-313). We appreciate their
regret that due to methodological problems results may not be as clear-cut
as they desire.
The study of potential effects of emissions from mobile phone base-
stations is indeed fraught with intriguing methodological problems,
however, we admit that those raised by Wolf and Vana are not among those
we were primarily concerned about.
1. Concerning the problem of random clustering that could reduce
effective sample size via a joint influence of an unknown factor on one or
several outcome variables on all subjects within that cluster, we have
taken substantial precaution, in the statistical and material sense. We
did all analyses first by inclusion of the base-station as a random factor
(the variance component of which is equivalent to the intra-class
correlation). These analyses revealed no indication of clustering.
Furthermore, we measured in homes of participants in the urban area
volatile organic compounds and did ambient noise measurements in the rural
area. There were no differences between base-stations in these
environmental factors and no correlation between exposure to
electromagnetic fields and indoor VOC concentrations was detected.
2. Strong concerns were expressed by 8% of participants and there was
indeed a correlation with distance to the base station and, to a lesser
degree, also with exposure category (mean ratings on a scale 0 to 3 were
0.7, 0.9, and 1.3 for the exposure categories, respectively). Hence
concerns about adverse effects of base-stations is indeed a confounding
variable because, as we stated in the discussion, it was also correlated
with many symptoms. Likert type scale of concerns was area transformed
before inclusion into ANCOVA.
3. Dichotomisation of symptoms of the Zerssen Scale was done applying
the only objective cut-off, i.e. discriminating between those that did not
experience this symptom from those that did (thereby neglecting strength
of symptoms). The reasons for applying a dichotomisation were manifold,
but the most important one was to enable usage of the same method of
evaluation for all symptoms. Some symptoms were never or only rarely
categorized into the highest category and therefore applying ordinal
regression led to parameter identification problems. Scoring several
symptoms together into groups of symptoms has not found approval by
reviewers.
4. It is correct that the model of analysis must be set beforehand.
Therefore, results were given for the model as specified. However, to give
an idea about the effect of loss of power by inclusion of insignificant
covariables, following reviewers' suggestions, also the result after their
omission was presented in one case. Application of the Bonferroni or
Bonferroni-Holm method is up to the reader. He/she should only be aware
that this method is utterly conservative and will substantially increase
type II error in the case of correlations between dependent variables
(which is the rule for symptoms, performance variables, and sleep quality
indices). In exploratory studies that cannot start from evidence based
hypotheses such correction will render even much bigger trials practically
powerless and is therefore not recommended.
5. We have clearly stated that we did not apply correction for
multiple testing. We have therefore employed caution in interpretation of
results. Based on our study future investigations can be planned and
evaluated more rigorously. But awaiting more and better evidence should
not prevent us from recommending a minimisation strategy for the siting of
mobile phone base-stations. How to implement such strategies without
evoking the problem Prof. Coggon pointed to in his commentary, that
precautionary measures might distort risk perception thereby potentially
inducing reduced wellbeing and health, could be a task most suited to
Profs. Wolf and Vana that are presiding an advisory board of the Austrian
Federal Ministry of Transport, Innovation and Technology.
We appreciate the interest of Dr. Garlantezec and colleagues in our
article on the association between maternal occupational exposure to
organic solvents (chlorinated, aromatic and Stoddard) and birth defects.
We reported a positive association between chlorinated solvents and neural
tube defects, particularly spina bifida; we did not observe an association
between solvent exposure and orofacial clefts.
We appreciate the interest of Dr. Garlantezec and colleagues in our
article on the association between maternal occupational exposure to
organic solvents (chlorinated, aromatic and Stoddard) and birth defects.
We reported a positive association between chlorinated solvents and neural
tube defects, particularly spina bifida; we did not observe an association
between solvent exposure and orofacial clefts.
As noted in their comment, our exposure assessment did not include
oxygenated solvents such as glycol ethers, which have been previously
linked with an increased prevalence of some birth defects, including both
oral clefts and neural tube defects. Garlantezec et al. suggest that our
exclusion of oxygenated solvents may explain our null findings for oral
clefts because women exposed to such solvents may be included in our
reference group, thereby introducing bias. Though potentially a plausible
explanation for our findings, we believe that bias due to the lack of
assessment for oxygenated solvents is unlikely. Based on preliminary,
unpublished data from an expert industrial hygienist review-based
assessment for the National Birth Defects Prevention Study, only 0.4
percent of working women in our study population had any exposure to
glycol ethers during pregnancy or the 3 months before conception. Because
the prevalence of occupational exposure to glycol ethers in our study
population is exceedingly rare, its omission would not result in a
meaningful underestimate of our effect measure estimates. However,
estimated exposure to other oxygenated solvents such as aliphatic
alcohols, ketones, esters and aldehydes in our study population is
unknown.
We agree with Dr. Garlantezec and colleagues that differences in the
definition of exposure (characterized by solvent type, formulation or
mixture, frequency and intensity, etc., as noted in our Discussion) may
explain apparent "inconsistencies" in reported results across studies. We
encourage further dialogue and research aimed at elucidating the true
underlying relation between exposure to distinct classes of organic
solvents and birth defects.
It is disturbing that the Interphone study group first publishes
several papers purportedly finding negative results but only now
publishes a validation study showing that the methods used to measure
exposure are so deeply flawed that it was unlikely the previously
published studies would detect an increase in risk of brain tumour in
mobile phone users(1).
It is disturbing that the Interphone study group first publishes
several papers purportedly finding negative results but only now
publishes a validation study showing that the methods used to measure
exposure are so deeply flawed that it was unlikely the previously
published studies would detect an increase in risk of brain tumour in
mobile phone users(1).
In the validation study of 672 volunteers recall of phone use over a
3-8 months period about six months later, was compared with objective data
from phone bills and use of special soft-ware modified phones. The study
found large random errors in recall which can be expected to have a “large
impact” and bias risk estimates toward a null effect. There was also a
wide variation between countries which further emphasises the randomness
of recall (and the difficulty in conducting a meta-analysis of results
from participating countries). Moreover the validation study design
minimises the errors of recall for several reasons. It largely used
"colleagues and acquaintances of the investigators". These volunteers
would have been well informed of the intent of the study and the
importance of accurately recalling mobile phone usage, and are therefore
different from the naïve subject in the actual studies whose recall would
be even more random. Also the validation study only sought recall of
mobile phone use for 3-8 months about six months later, whereas in the
actual studies recall for up to 10 years was sought which is likely to
lead to even more randomness in recall. The validation study did not
address the problem of impaired recall in the cases with brain tumours who
are likely to have their memory affected from their tumour and subsequent
surgery, radiotherapy, chemotherapy and psychological distress, let alone
the accuracy of surrogates (spouses) used in some studies.
The validation study reveals at a minimum the flawed methodology
being used in the Interphone studies which would lead to Type2 (false
negative) errors thus lessening the ability to except with confidence the
published negative papers regarding the health effects of mobile
phones(2). The late publication of a key methods paper after publication
of many results papers raises concerns about the processes within the
Interphone study group.
Yours
Dr Bruce Hocking.
References
1. Vrijheid M, Cardis E, Armstrong BK, Auvinen A, Berg G, Blaasaas
KG, Brown J, Carroll M, Chetrit A, Christensen HC, Deltour I, Feychting M,
Giles GG, Hepworth SJ, Hours M, Iavarone I, Johansen C, Klaeboe L, Kurttio
P, Lagorio S, Lonn S, McKinney PA, Montestrucq L, Parslow RC, Richardson
L, Sadetzki S, Salminen T, Schuz J, Tynes T, Woodward A; Interphone Study
Group. Validation of short term recall of mobile phone use for the
Interphone study. Occup Environ Med. 2006 Apr;63(4):237-43.
2. Hocking B. Mobile phone use and risk of acoustic neuroma.
Br J Cancer. 2006 May 8;94(9):1350; author reply 1352-3.
Editor,-
I welcome the publication of recent papers by Cherry and her collaborators.[1] [2] Although they form part of a large number of epidemiological studies, referenced by the authors, based solely on questionnaire data they do add significantly to the understanding of the ill-health of Gulf War Veterans (GWVs). The limitations of such studies are recognised by the authors, for example, the lack of any bas...
Dear Editor,
It has been clear for years, based on much published research, that symptoms in office workers are associated with a number of environmental factors in office buildings and also, independently, with psychosocial stressors at work. So we were surprised to see a recent article by Marmot et al. (1) report that, in offices in the Whitehall II Study, “raised symptom levels appear to be largely due to a...
Editor
with regard to the limit of detection and to the data in table 5 and figure 5, the level of benzene in blood has given in µg/l. I believe that the correct indication should be in ng/l. As matter of fact, with a personal exposure to benzene of 9.3-3.8 µg/m3, it is impossible to have a blood benzene level of 213-195 µg/l which should be corresponding to an environmental exposure to benzene of more than...
Dear Authors,
Thank you for the great editorial. I would like to suggest that given your experience, especially Dr. Hoppin, it would be especially helpful to formulate more specific proposals for introducing at the state level, including California. The University of California, as an example, has been largely unresponsive to requests for disclosures regarding potential conflict of interest situations for facu...
Editor-
Meredith et al,[1] performed a case referent study to investigate asthma caused by isocyanates. They claimed that the results indicated that isocyanate asthma occurs at low 8h average exposure (around 1.5 ppb); for exposures above 1.125 ppb there was about a three fold increased risk, however this was of limited statistical significance (OR=3.2, 95% CI 0.96- 10.6; p=0.06). They also concluded that their s...
Dear Editor,
In their publication, the authors postulate that effects upon health and performance cannot be ruled out despite a low exposure to high-frequency electro-magnetic fields, effects far below the WHO threshold values. Unfortunately, this paper has substantial methodological problems.
1. There may well have been a clustering in the choice of test- subjects’ addresses in relation to the location...
We read with interest the report by Desrosiers et al of the association between maternal occupational exposure to organic solvents and some birth defects [1]. Their case-control study examined occupational exposure to three classes of solvents (chlorinated, aromatic and Stoddard) and found one association -- between neural tube defects (mainly spinal bifida) and maternal occupational exposure to chlorinated solvents, but n...
Dear Editor,
We thank Wolf and Vana for their comments on our article "Subjective symptoms, sleeping problems and cognitive performance in subjects living near mobile phone base-stations" (OEM 63:307-313). We appreciate their regret that due to methodological problems results may not be as clear-cut as they desire.
The study of potential effects of emissions from mobile phone base- stations is indeed fr...
We appreciate the interest of Dr. Garlantezec and colleagues in our article on the association between maternal occupational exposure to organic solvents (chlorinated, aromatic and Stoddard) and birth defects. We reported a positive association between chlorinated solvents and neural tube defects, particularly spina bifida; we did not observe an association between solvent exposure and orofacial clefts.
As noted...
Dear Editor,
It is disturbing that the Interphone study group first publishes several papers purportedly finding negative results but only now publishes a validation study showing that the methods used to measure exposure are so deeply flawed that it was unlikely the previously published studies would detect an increase in risk of brain tumour in mobile phone users(1).
In the validation study of 672 vo...
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