In his electronic letter, Dr Murphy wrote that the 55% response rate from the doctors could have considerably biased the results reported in a study of sickness absence in Finnish hospital physicians.[1] According to the results, absence rate for doctors is low. The study also suggests
that poor teamwork and traditional psychosocial risk factors, such as work overload and low job control, contribute to doctors'...
In his electronic letter, Dr Murphy wrote that the 55% response rate from the doctors could have considerably biased the results reported in a study of sickness absence in Finnish hospital physicians.[1] According to the results, absence rate for doctors is low. The study also suggests
that poor teamwork and traditional psychosocial risk factors, such as work overload and low job control, contribute to doctors' long-term sick leaves.
As already reported in the article (p. 362), hospital registers show that low response rate did not affect the findings on absence rates. In those who responded to the survey, the rate of short-term (1-3 days) sickness absences was 38.0 spells per 100 person-years. The corresponding
rate for the eligible population was 37.9 spells per 100
person-years. Regarding the rate of long-term (>3 days) sickness absences, the rate was exactly the same for the respondents and the eligible population, ie,
20.2 long sickness absence spells per 100 person-years.
Bias due to low response rate seems also unlikely in relation to
psychosocial factors. In work units with a response rate lower than 55%, the mean scores of teamwork and job control were 3.5 and 4.0, respectively. In work units with a response rate of 55% or higher, the corresponding mean scores were also 3.5 and 4.0, respectively. In the
overload scale, the mean score of 3.8 in the low-response-rate units
did
not differ from the mean score of 3.6 in the high-response-rate units
(P
value 0.130).
Dr Murphy acknowledges that incomplete recording of sickness
absences
could also affect the results and conclusions. However, at least the
following points suggest that the recording of doctors' long-term
sickness
absences was reliable.
First, Finnish hospitals receive compensation for loss of salary
due
to sick leaves longer than 10 days from the Social Insurance
Institution,
a body subordinate to Parliament. To receive all the compensations to
which the hospitals are entitled, they are motivated to keep strict
records of sick leaves. This was especially true during the study
period.
Hospitals had shortage of financial resources compared to the amount
of
services they were expected to provide.
Second, indicators of health problems, such as poor self-rated
health, presence of diagnosed chronic disease, and psychiatric
morbidity
(as indicated by GHQ-caseness), were associated with long spells of
sickness absence (see Table 3 in the article).[1] For doctors, these
associations were as strong as or stronger than those found for the
controls. Only the opposite case, ie if the associations had been
weaker
for doctors, could have been an indication of unreliable measurement
of
doctors' sickness absence.
Third, the finding of low recorded absence rate for hospital
physicians is well in line with other research. Results on
self-reported
absences in a random sample of Finnish physicians suggest that
physicians
are on sick leave much less often than other employees.[2] According
to a
British study, over 80% of physicians had worked even when they felt
too
unwell to carry out their duties to the best of their ability.[3] A
Norwegian study reports that 80% of the physicians had worked during
an
illness for which they would have sick-listed their patients.[4]
In conclusion, evidence and additional analyses provide no
support
for the possibility that the issues listed by Dr Murphy would have
added
bias to the study on sickness absence in Finnish hospital physicians.
Prof. Mika Kivimaki
Department of Psychology
University of Helsinki
Finland
References
(1) Kivimaki M, Sutinen R, Elovainio M, et al. Sickness absence
in
hospital physicians: 2 year follow up study on determinants. Occup
Environ
Med 2001;58:361-366.
(2) Toyry S, Rasanen K, Kujala S, et al. Self-reported health,
illness,
and self-care among Finnish physicians: a national survey. Arch Fam
Med
2000;9:1079-1085.
(3) McKevitt C, Morgan M, Dundas R, Holland WW. Sickness absence and
'working through' illness: a comparison of two professional groups. J
Public Health Med 1997;19:295-300.
(4) Rosvold EO, Bjertness E. Physicians who do not take sick leave:
hazardous heroes. Scand J Public Health 2001;29:71-75.
Kivimaki and colleagues [1] undertook research to identify some
determinants of sickness absence in Finnish hospital physicians between
1997 and 1998. This was a questionnaire survey sent to 816 physicians and
a control group of 542 senior nurses employed in one of 11 hospitals in
Finland. Social circumstances, work characteristics and various measures
of health were assessed by questionnaire and e...
Kivimaki and colleagues [1] undertook research to identify some
determinants of sickness absence in Finnish hospital physicians between
1997 and 1998. This was a questionnaire survey sent to 816 physicians and
a control group of 542 senior nurses employed in one of 11 hospitals in
Finland. Social circumstances, work characteristics and various measures
of health were assessed by questionnaire and employers' registers were
used to assess recorded sickness absence.
There are some limitations in the study design and subsequent
conclusions that are not acknowledged in the text.
The response rate from the physicians was a disappointing 55%. Nearly
half of the physicians approached did not participate in the study. This
could bias the results considerably. The authors state that the response
rate obtained in this study corresponds to that obtained in previous
research. Seven references are cited as evidence. The response rates of
doctors from six of the seven quoted papers are higher than 55% and are as
follows: 82% [2]; 79% and 76% [3]; 63% [4]; 78% [5]; 58% [6]; and 87% to
94% [7]. The authors could have cited a further reference [8] that was
used later in the paper, but chose not to (response rate 80%).
The authors state that the recording of attendance is reliable in the
Finnish public sector. This would be a very important factor in the
context of this study of sickness absence in hospital physicians. The
authors cite two references [9,10] to back up their statement. These two
studies both concern local government workers in Raisio, Finland between
1990 and 1995 with the main outcome measure being recorded medically certificated absence held on computer by an occupational health unit. Both
of these papers simply state that all sick certificates must be forwarded
for recording, but provide no other evidence that the recording of
sickness absence is reliable. The possibility that doctors might under report sickness absence, leading to incomplete recording, is not
considered. This could add further bias to the study, thereby affecting
the results and conclusions.
Dr Ian J Murphy
Specialist Registrar in Occupational Medicine
Royal Berkshire and Battle Hospitals NHS Trust
References
(1) Kivimaki M, Sutinen R, Elovainio M, et al. Sickness absence in
hospital physicians: 2 year follow up study on determinants. Occupational
and Environmental Medicine 2001;58:361-6.
(2) Chambers R, Belcher J. Comparison of the health and lifestyle of
general practitioners and teachers. British Journal of General Practice
1993;43:378-82.
(3) McKevitt C, Morgan M, Dundas R, et al. Sickness absence and
"working through" illness: a comparison of two professional groups.
Journal of Public Health Medicine 1997;19:295-300.
(4) Waldron HA. Sickness in the medical profession. Annals of
Occupational Hygiene 1996;40:391-6.
(5) Ramirez AJ, Graham J, Richards MA, et al. Mental health of hospital
consultants: the effects of stress and satisfaction at work. Lancet
1996;347:724-8.
(6) Deckard G, Meterko M, Field D. Physician burnout: an examination of
personal, professional and organisational factors. Medical Care
1994;32:745-54.
(7) Johnson JV, Hall EM, Ford DE, et al. The psychosocial work
environment of physicians. J Occup Environ Med 1995;37:1151-9.
(8) Caplan RP. Stress, anxiety and depression in hospital consultants,
general practitioners and senior health service managers. BMJ
1994;309:1261-3.
(9) Kivimaki M, Vahtera J, Pentti J, et al. Factors underlying the
effect of organisational downsizing on health of employees: longitudinal
cohort study. BMJ 2000;320:971-5.
(10) Vahtera J, Kivimaki M, Pentti J. Effect of organisational
downsizing on health of employees. Lancet 1997;350:1124-8.
In their recent short report,[1] O'Connor et al. describe a case of
occupational asthma due to the enzymes phytase and ß-glucanase. Their
patient experienced asthma-like symptoms at work (wheezing and cough), had
positive skin prick tests and specific IgE to both enzymes (by
radioallergosorbent test), and reacted to both materials in separate
inhalation challenge tests. None of 22 other employees in...
In their recent short report,[1] O'Connor et al. describe a case of
occupational asthma due to the enzymes phytase and ß-glucanase. Their
patient experienced asthma-like symptoms at work (wheezing and cough), had
positive skin prick tests and specific IgE to both enzymes (by
radioallergosorbent test), and reacted to both materials in separate
inhalation challenge tests. None of 22 other employees in the same factory
were reported to have experienced respiratory symptoms at work1.
In a German language paper presented at the 38th Annual Meeting of
the German Association of Occupational and Environmental Medicine in
1998,[2] we reported findings of a systematic clinical investigation of 49
research and development (R+D) employees working with the enzymes phytase
and xylanase. This investigation was undertaken after detecting airway
sensiti-sation to phytase-containing dusts in two analytical laboratory
employees.
Forty nine employees with potential enzyme contact completed a
question-naire and underwent physical examination and lung function
testing. Among 32 employees with findings of conjunctivitis, rhinitis, or
bronchitis, further immunologic tests were undertaken on a voluntary basis
(skin prick test,
n = 17; specific IgE by enzyme allergosorbent test (EAST), n = 31). In
addi-tion, nasal provocation challenge tests were performed in 13
employees, including all eleven with a positive skin prick test to
phytase. Nine of these employees had a positive specific IgE test to
phytase as well. All eleven had a positive nasal challenge response to
phytase. The positive response rate was 62.5% among eight employees
considered to have the highest potential exposure. Based on this
investigation, it was concluded that phytase has a high sensitising
potency. In this regard our assessment is consistent with those of
O'Connor et al and Doekes et al.[1] [3]
After implementation of extensive control measures to prevent enzyme
expo-sure in this R+D facility, all employees now report being free of
work-related respiratory symptoms. This favorable experience is in
agreement with the the-sis that enzyme-related asthma can be avoided by
implementing best practice procedures for health surveillance and
environmental control when working with enzymes.[4]
A ZOBER
K STRASSBURGER
Occupational Medical and Health Protection Department
BASF Aktiengesellschaft
67056 Ludwigshafen, Germany
X BAUR
University of Hamburg
22083 Hamburg, Germany
References
(1) O'Connor TM, Bourke JK, Jones M, et al. Report of occupational
asthma due to phytase and ß-glucanase. Occup Environ Med 2001;58:417-19.
(2) Straßburger K, Bossert J, Baur X, et al. Sensibilisierung durch die
Enzyme Phytase and Xylanase. In: Hallier E, Bünger J, eds.
Dokumentationsband über die 38. Jahrestagung der Deutschen Gesellschaft
für Arbeitsmedizin und Umweltmedizin. Lübeck: 1998:525-7 (ISBN: 3-7900-
0302-6).
(3) Doekes G, Kamminga N, Helwegen L, et al. Occupational IgE
sensitisation to phytase, a phosphatase derived from Aspergillus niger.
Occup Environ Med. 1999;56:454-9.
(4) Nicholson PJ, Newman Taylor AJ, et al. Current best practice for
the health surveillance of enzyme workers in the soap and detergent
industry. Occup Med. 2001;51:81-92.
Chen et al report irritant symptoms experienced by dockyard painters
in both Scotland and China [1]. In 1985, I reported [2] on dockyard
painters involved in submarine refit work in one of HM's dockyards in
England. I too found a high prevalence of symptoms of irritation.
However, and possibly of more concern, the painters in my study also
reported narcotic symptoms. In 106 painters, 74 (70%) rep...
Chen et al report irritant symptoms experienced by dockyard painters
in both Scotland and China [1]. In 1985, I reported [2] on dockyard
painters involved in submarine refit work in one of HM's dockyards in
England. I too found a high prevalence of symptoms of irritation.
However, and possibly of more concern, the painters in my study also
reported narcotic symptoms. In 106 painters, 74 (70%) reported episodes
of light-headedness. Some 28 (26%) reported that, on occasion, this had
led them to stop painting and seek fresh air. 75 (71%) reported a solvent-
taste in their mouth - some reported their partners complaining of a
solvent-smell to their breath persisting into the evening after a day
shift.
The full-face air-fed masks then meant to be in use as respiratory
protective equipment were considered to be bulky, uncomfortable and to
restrict vision. They were almost universally disliked; instead, some
painters preferred to wear half-face masks and tolerate eye irritation
from the paint vapours - and for "touch ups" sometimes used no RPE.
The messages were that painters, and perhaps their supervisors as
well, needed to be reminded of the significance of narcotic symptoms; if
a less potentially-toxic paint system could not be found, additional
consideration needed to be paid to ventilation and a search made for a
more comfortable air-fed mask.
My study pre-dated both COSHH [3] and PPE Regulations [4]: one might
have hoped that their principles and implementation would have led to
fewer irritant symptoms than still apparently being experienced by Chen et
al's groups. Finally, in addition to the points in their paper, I would
suggest occupational physicians with painters in their care remain
vigilant for narcotic symptoms. There seems to remain scope for improved
control.
G WOODROOF
Occupational Health & Safety Unit
Derriford Hospital
Plymouth PL6 8DH, UK
References
(1) Chen R, Semple S, Dick F, Seaton A. Nasal, eye, and skin irritation
in dockyard painters. Cccup Environ Med 2000: 58; 542-543
(2) Woodroof G. Submarine painting: a cross-sectional epidemiological
investigation into work-related symptoms and lung function. J roy nav med
Serv. 1985; 71: 98-100
(3) Control of Substances Hazardous to Health Regulations, 1988. Health
& safety Commission
(4) Personal Protective Equipment at Work Regulations, 1992. Health
& safety Commission
We are grateful to Dr Jarvolm for his comments on our paper. The
specified aim of our study was to quantify the relationship between the
level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work
force, possibly with a nested case referent analysis. A register based
case referent study of the type described by Dr Jarvol...
We are grateful to Dr Jarvolm for his comments on our paper. The
specified aim of our study was to quantify the relationship between the
level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work
force, possibly with a nested case referent analysis. A register based
case referent study of the type described by Dr Jarvolm would be
unsuitable for this purpose because the source population would be ill defined, selection of a appropriate referents difficult, and reliable
assessment of their exposure almost impossible. We used the SWORD
reporting scheme, not as a register, but as a convenient means of
identifying workplaces from which clusters of asthma cases attributed to
isocyanates have been reported, and in which isocyanate exposure had been
assessed by an occupational hygienist; we then investigated those sites. In fact, a small number of additional cases were identified during the
course of the investigation and were included in the analysis. In company
A, where the majority of our cases worked, all employees were
subject to close respiratory supervision throughout their employment,
including pre-employment assessment; in company B, the occurrence of the
cluster of cases was recognised by the occupational health department and
the workers in the relevant areas investigated. We are therefore
reasonably confident that no cases were missed.
We were careful to select referents from workers who were exposed to
isocyanates and were under the same level of surveillance as the cases to
avoid some of the biases outlined by Dr Jarvolm. We agree that the close
matching of cases and referents probably reduced the sensitivity of the
study, but we felt that it was more important to do that than to risk
selection bias as described in his second hypothetical scenario. As we
also acknowledged in the article, we cannot exclude the theoretical
possibility that the cases of asthma were not caused by isocyanates, but
by other chemicals present in the plants. Confounding is a risk in any
observational study, although not necessarily a source of bias, but the
other agent would have to be closely correlated with the isocyanate
exposure to account for our findings.
The cases had work related asthma as diagnosed by an occupational
physician. Nearly all had a history of symptoms associated with work that
improved on days away from work and had had serial respiratory function
tests that supported the diagnosis. Challenge tests are rarely used in
the UK; very few centres undertake them, and without proper facilities are
considered dangerous. However, as explained in the article, in company A
persons with respiratory symptoms were removed from exposure to
isocyanates until they had recovered and then gradually returned to their
previous work under very close supervision with serial respiratory
function testing, which in practice was a form of challenge test.
The purpose of undertaking a case referent study was not to establish
that it is possible to develop isocyanate asthma at low exposures, but to
examine the exposure response relationship. We do not conclude from our
data that there is a threshold below which isocyanate exposure is safe. The level of 1.25 ppb was arbitrarily chosen because it was the median time weighted average exposure in the referent group in company A. Despite
the fact that all estimated eight hour TWA exposures were within the maximum
exposure limits, those subjects whose estimated eight hour TWA was greater
than 1.25 ppb appeared to be at increased risk of occupational asthma. However, the data were also compatible with a linear exposure response
relationship in which the odds of asthma increased by 1.08 for every
0.1ppb. A much larger study would be needed to test these two possible
exposure-response relationships fully.
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.
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
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.
Dr Burge and his coworkers raise a very important issue in terms of the physiological criteria on which a diagnosis of occupational asthma should be based, and in particular, the clinical significance of small work related declines in peak expiratory flow. We fully accept that a lack of an increase in diurnal variation does not exclude a diagnosis of occupational asthma. The pattern of peak flow measurements...
Dr Burge and his coworkers raise a very important issue in terms of the physiological criteria on which a diagnosis of occupational asthma should be based, and in particular, the clinical significance of small work related declines in peak expiratory flow. We fully accept that a lack of an increase in diurnal variation does not exclude a diagnosis of occupational asthma. The pattern of peak flow measurements in occupational asthma quite frequently reveals a marked difference in the mean peak flow on working days compared to days away from work without any increase in
diurnal variation.
Dr Burge and his colleagues refer to the phenomenon of small work related changes and raise the question as to whether this represents asthma or other lung pathology.[1] At that time, their opinion was that the significance of these small changes was unclear. The example that they gave showed that taking the lowest peak flow recording during the working week and the highest peak flow recording on days away from work, a variation in peak flow in excess of 20% which we would accept as compatible with asthma and from the pattern
illustrated probable occupational asthma. The small group of workers that we studied had diurnal variations in peak flow ranging between 5.7% and 9.8% and taking the worst working day peak flow and the best day off work peak flows, a variation between 11% and 13.5% (our peak flow recordings
were linearised). This degree of variation does not satisfy the BTS criteria for a diagnosis of bronchial asthma, neither do they satisfy a positive challenge response in bronchial challenge study. We have seen similar
patterns of peak flow recordings in textile workers exposed to dust, both with and without, significant contamination with endotoxin.
We took the view that the small peak flow changes were due to an irritant effect and postulate the same mechanism in this group exposed to glutaraldehyde. The
clinical histories provided by these workers does not suggest increasing
respiratory symptoms with continued exposure. While it is possible that
the changes that we have reported may represent a very mild form of
occupational asthma, the clinical picture and the small physiological
variation in peak flow, in our opinion is more consistent with
an irritant airway response than the development of occupational asthma.
Our paper is not intended to suggest that glutaraldehyde is not capable of inducing occupational asthma, for which there is convincing published evidence, in addition to our own personal experience. Our paper reports the findings of an epidemiological survey of a large population of
currently exposed endoscopy nurses and has demonstrated that while respiratory symptoms occur in this group, that the lung physiology and the immunology has not supported a suggestion of a high prevalence of occupational asthma
at current exposure levels.
We appreciate the interest taken in our study by Dr. Freedman.[1] At the heart of the discussion are the interpretation of statistical significance in our study,[2] and the lack of statistical significance in others. A critical point in valuing causation is the weight of the evidence to be placed upon the nonsignificant increase of nonspecific exposures observed in human studies of amyotrophic lateral sclerosis (ALS) compare...
We appreciate the interest taken in our study by Dr. Freedman.[1] At the heart of the discussion are the interpretation of statistical significance in our study,[2] and the lack of statistical significance in others. A critical point in valuing causation is the weight of the evidence to be placed upon the nonsignificant increase of nonspecific exposures observed in human studies of amyotrophic lateral sclerosis (ALS) compared to the
weight placed upon controlled animal studies specific to the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D).
I agree with Dr. Freedman that undue reliance upon statistical significance is ill advised. He is correct that the case-control studies cited in our paper showed elevated odds ratios,[3][4][5][6] but there is no evidence that any subjects were actually exposed to 2,4-D since the exposures were limited to "pesticides" and "agricultural chemicals" and "herbicides". The cohort studies examined workers who were definitely exposed to 2,4-D and thus provide a more valid assessment of risk even though they are less powerful than the case-control studies.[7][8] The cohort studies of 2,4-D do not consistently show increased risk of ALS.
The associations observed in the case-control studies are clearly unsupported by the experimental studies that have been conducted on 2,4-D. Environmental causes of ALS remain unknown. If future epidemiological studies investigate the neurotoxicity of herbicides such as 2,4-D, the researchers must improve upon the status quo of surrogate exposure
information used in case-control studies or perform further studies of the 2,4-D workers. Epidemiologist must make a commitment to quality exposure assessment of individual pesticides, perhaps coupled with biomonitoring, to address the putative health concerns associated with pesticides.
CJ Burns
1 Freeman DM. Mortality in chemical workers potentially
exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945 – 94: an update. Occup Environ Med 2001.
2 Burns CJ, Beard KKI, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid 1945-94: an update. Occup Environ Med 2001;58:24-30.
3 Chancellor AM, Slattery JM, Fraser H, et al. Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry 1993;56:1200-
6.
4 Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 1986;123:790-9.
5 Saviettieri G, Salemi G, Arcara A, et al. A case-control study of amyotrophic lateral sclerosis. Neuroepidemiology 1991;10:242-5.
6 McGuire V, Longstreth WT Jr, Nelson LM, et al. Occupational exposures and amyotrophic lateral sclerosis. Am J Epidemiol 1997;145:1076-88.
7 Zahm SH. Mortality study of pesticide applicators and other employees of a lawn care service company. J Occup Environ Med 1997;39:1055-67.
8 Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med 1991;48:173-8.
In his electronic letter, Dr Murphy wrote that the 55% response rate from the doctors could have considerably biased the results reported in a study of sickness absence in Finnish hospital physicians.[1] According to the results, absence rate for doctors is low. The study also suggests that poor teamwork and traditional psychosocial risk factors, such as work overload and low job control, contribute to doctors'...
Dear Editor,
Kivimaki and colleagues [1] undertook research to identify some determinants of sickness absence in Finnish hospital physicians between 1997 and 1998. This was a questionnaire survey sent to 816 physicians and a control group of 542 senior nurses employed in one of 11 hospitals in Finland. Social circumstances, work characteristics and various measures of health were assessed by questionnaire and e...
Dear Editor,
In their recent short report,[1] O'Connor et al. describe a case of occupational asthma due to the enzymes phytase and ß-glucanase. Their patient experienced asthma-like symptoms at work (wheezing and cough), had positive skin prick tests and specific IgE to both enzymes (by radioallergosorbent test), and reacted to both materials in separate inhalation challenge tests. None of 22 other employees in...
Dear Editor,
Chen et al report irritant symptoms experienced by dockyard painters in both Scotland and China [1]. In 1985, I reported [2] on dockyard painters involved in submarine refit work in one of HM's dockyards in England. I too found a high prevalence of symptoms of irritation. However, and possibly of more concern, the painters in my study also reported narcotic symptoms. In 106 painters, 74 (70%) rep...
Editor-
We are grateful to Dr Jarvolm for his comments on our paper. The specified aim of our study was to quantify the relationship between the level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work force, possibly with a nested case referent analysis. A register based case referent study of the type described by Dr Jarvol...
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...
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...
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...
Editor
Dr Burge and his coworkers raise a very important issue in terms of the physiological criteria on which a diagnosis of occupational asthma should be based, and in particular, the clinical significance of small work related declines in peak expiratory flow. We fully accept that a lack of an increase in diurnal variation does not exclude a diagnosis of occupational asthma. The pattern of peak flow measurements...
We appreciate the interest taken in our study by Dr. Freedman.[1] At the heart of the discussion are the interpretation of statistical significance in our study,[2] and the lack of statistical significance in others. A critical point in valuing causation is the weight of the evidence to be placed upon the nonsignificant increase of nonspecific exposures observed in human studies of amyotrophic lateral sclerosis (ALS) compare...
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