Exposures recorded for participants in the UK Chemical Warfare Agent Human Research Programme, 1941-1989.

OBJECTIVES: This study describes exposures to military veterans who participated between 1941 and 1989 in British research at Porton Down on the effects of exposure to chemical warfare agents and to defences against those agents. The study is part of a programme of epidemiological research initiated in response to service veterans' concerns about possible long-term health effects of their participation. METHODS: All entries in 97 books held in the Porton Down historical experimental archive covering the years 1939-1989 were reviewed. For tests between April 1941 and December 1989, data were abstracted on chemicals used, with additional detail abstracted for tests involving vesicants and nerve agents. For tests recorded during 1939-1941, similar data were abstracted for a representative sample of tests. RESULTS: Historical data were abstracted for 17 303 veterans included in the cohort study of 18,276 servicemen who took part in tests at Porton Down between 1941 and 1989. The median number of days per veteran on which tests were carried out was 2 days. The median difference between the last and first day of testing was 4 days. A large number of chemicals were tested over this period (n = 492). The type of chemical tested varied over time. Exposures were often modified by respirator use or use of protective clothing or protective equipment. It was possible to assign a quantitative measure of cumulative exposure to 73% of veterans exposed to the vesicant sulphur mustard--3491 (34%) of exposed veterans had cumulative exposures > or =10.63 mg and for 70% of veterans exposed to the nerve agent sarin--658 (29%) of exposed veterans had cumulative exposures > or =15.0 mg min m(-3). Ninety-three per cent of veterans exposed to sulphur mustard were classified to a semi-quantitative scale of dermal effect--3771 (37%) had a vesicle or necrosed area, and 69% of veterans exposed to sarin could be categorized by change in blood cholinesterase activity--1033 (31%) had a depression in cholinesterase activity of > or =30%. CONCLUSIONS: The experimental archive at Porton Down has proved to be a rich source of data on tests conducted between 1941 and 1989. It has been possible to categorize most veterans according to date of test, chemical group, chemical, type of protection and, for certain chemicals, level of exposure and/or degree of acute toxicity. These categorizations have been used to assign veterans to exposure groups for epidemiological analysis.

Occupational health needs of universities: a review with an emphasis on the United Kingdom.

This study describes the needs of universities in relation to planning the provision of occupational health services, by detailing their occupational hazards and risks and other relevant factors. The paper presents the results of (1) an enquiry into publicly available data relevant to occupational health in the university sector in the United Kingdom, (2) a literature review on occupational health provision in universities, and (3) selected results from a survey of university occupational health services in the UK. Although the enquiry and survey, but not the literature review, were restricted to the UK, the authors consider that the results are relevant to other countries because of the broad similarities of the university sector between countries. These three approaches showed that the university sector is large, with a notably wide range of occupational hazards, and other significant factors which must be considered in planning occupational health provision for individual universities or for the sector as a whole.

Consequences of occupational asthma.

Seventy-nine patients attending hospital for follow-up of occupational asthma were interviewed, on average 6 years after asthma developed. Although 90% thought their symptoms had improved, 10% had required a hospital admission (apart from for investigation), 72% still took medication and most reported symptoms in the last 3 months. One-third were currently unemployed and 40-73% reported limitation in everyday activities, such as housework or shopping. Symptoms on waking were used as an index of troublesome asthma. Those 31 in whom this occurred at least once a week reported limitation in everyday activities significantly more commonly than others. This relation was more marked in men than women. Limitation in everyday activities was, however, more frequently reported by women than men, who were also more likely than men to be unemployed, suggesting that factors other than impairment of function also contribute to handicap in occupational asthma.

Exposure-response relations for work related respiratory symptoms and sensitisation in a cohort exposed to alpha-amylase.

AIMS: To explore relations between exposure to fungal alpha-amylase and the risk of new work related respiratory symptoms or sensitisation. METHODS: A prospective cohort study among 300 bakers and millers was followed up for a maximum of seven years. Exposure to alpha-amylase was estimated by air measurements and questionnaires and classified into three categories. Symptoms were recorded with a self-administered questionnaire and skin sensitisation assessed using skin prick test (SPT). RESULTS: There were 36 new cases of chest symptoms, 86 of eyes/nose symptoms, and 24 of a positive SPT to alpha-amylase. There were exposure-response relations for chest and eyes/nose symptoms and for sensitisation, and a significantly increased prevalence ratio for chest symptoms in the highest exposure category. CONCLUSION: A reduction in alpha-amylase exposure is likely to reduce the risk for respiratory morbidity in bakery workers.

Bronchial responsiveness and the reproducibility of forced expiratory volume in one second.

Although poorly reproducible spirometric tests, "test failures," are associated with respiratory morbidity, it is not clear what causes them. Bronchial responsiveness was examined in relation to test failure for forced expiratory volume in 1 s (FEV1.0) (1979 definition of the American Thoracic Society) in 249 bakers, 165 chemical industry workers, and 204 office workers. The first two groups were studied by the same methods and were combined. Test failure was observed in 4%, and for 38% the provocative dose of inhaled methacholine causing a 20% fall in FEV1.0 relative to FEV1.0 after the inhalation of normal saline (PD20) was < or = 120 mumol (7% with a PD20 of < or = 8 mumol). Test failure was not related to the level of PD20. Of the office workers, 3% had test failure, 11% a PD20 of < or = 8 mumol of histamine, and no significant relation was observed. The study does not exclude the possibility that bronchial responsiveness might be related to test failure in patients with airway disease or that a clearer relation might be demonstrable in a larger study, but it does suggest that it is not a major determinant of test failure.

A major outbreak of asthma associated with a thunderstorm: experience of accident and emergency departments and patients' characteristics. Thames Regions Accident and Emergency Trainees Association.

OBJECTIVE: To investigate the time course of an epidemic of asthma after a thunderstorm, characteristics of patients affected, and the demand on emergency medical resources. DESIGN: Study of registers and records in accident and emergency departments and questionnaire to staff. SETTING: London area. SUBJECTS: All patients presenting at 12 accident and emergency departments with asthma or other airway disease. MAIN OUTCOME MEASURES: Numbers of patients, clinical features, information on shortage of resources--equipment, drugs and staff. RESULTS: The epidemic had a sudden onset on 24 June 1994; 640 patients with asthma or other airways disease attended during 30 hours from 1800 on 24 June, nearly 10 times the expected number. Over half (365) the patients were aged 21 to 40 years. A history of hay fever was recorded in 403 patients; for 283 patients this was the first known attack of asthma; a history of chronic obstructive airways disease was recorded in 12 patients. In all, 104 patients were admitted (including five to an intensive care unit). Several departments ran out of equipment or drugs, called in additional doctors, or both. CONCLUSIONS: This study supports the view that this epidemic was larger than previously reported epidemics and the hypothesis that "thunderstorm associated asthma' is related to aeroallergens. Demands on resources were considerable; a larger proportion of patients needing intensive care would have caused greater problems.

Smoking and occupational allergy in workers in a platinum refinery.

OBJECTIVE: To test the hypothesis that smoking increases the risk of sensitisation by occupational allergens. DESIGN: Historical prospective cohort study. SETTING: Platinum refinery. SUBJECTS: 91 Workers (86 men) who started work between 1 January 1973 and 31 December 1974 and whose smoking habit and atopic state (on skin prick testing with common allergens) had been noted at joining. MAIN OUTCOME MEASURES: Results of skin prick tests with platinum salts carried out routinely every three to six months and records of any respiratory symptoms noted by the refinery's occupational health service. Follow up was until 1980 or until leaving refinery work, whichever was earlier. RESULTS: 57 Workers smoked and 29 were atopic; 22 developed a positive result on skin testing with platinum salts and 49 developed symptoms, including all 22 whose skin test result was positive. Smoking was the only significant predictor of a positive result on skin testing with platinum salts and its effect was greater than that of atopy; the estimated relative risks (95% confidence interval) when both were included in the regression model were: smokers versus non-smokers 5.05 (1.68 to 15.2) and atopic versus non-atopic 2.29 (0.88 to 5.99). Number of cigarettes smoked per day was the only significant predictor of respiratory symptoms. CONCLUSION: Smokers are at increased risk of sensitisation by platinum salts.

Mortality in British military participants in human experimental research into chemical warfare agents at Porton Down: cohort study.

OBJECTIVE: To investigate any long term effects on mortality in participants in experimental research related to chemical warfare agents from 1941 to 1989. DESIGN: Historical cohort study. Data sources Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. Participants 18,276 male members of the UK armed forces who had spent one or more short periods (median 4 days between first and last test) at Porton Down and a comparison group of 17,600 non-Porton Down veterans followed to 31 December 2004. MAIN OUTCOME MEASURES: Mortality rate ratio of Porton Down compared with non-Porton Down veterans and standardised mortality ratio of each veteran group compared with the general population. Both ratios adjusted for age group and calendar period. RESULTS: Porton Down veterans were similar to non-Porton Down veterans in year of enlistment (median 1951) but had longer military service (median 6.2 v 5.0 years). After a median follow-up of 43 years, 40% (7306) of Porton Down and 39% (6900) of non-Porton Down veterans had died. All cause mortality was slightly greater in Porton Down veterans (rate ratio 1.06, 95% confidence interval 1.03 to 1.10, P<0.001), more so for deaths outside the UK (1.26, 1.09 to 1.46). Of 12 cause specific groups examined, rate ratios in Porton Down veterans were increased for deaths attributed to infectious and parasitic (1.57, 1.07 to 2.29), genitourinary (1.46, 1.04 to 2.04), circulatory (1.07, 1.01 to 1.12), and external (non-medical) (1.17, 1.00 to 1.37) causes and decreased for deaths attributed to in situ, benign, and unspecified neoplasms (0.60, 0.37 to 0.99). There was no clear relation between type of chemical exposure and cause specific mortality. The mortality in both groups of veterans was lower than that in the general population (standardised mortality ratio 0.88, 0.85 to 0.90; 0.82, 0.80 to 0.84). CONCLUSIONS: Mortality was slightly higher in Porton Down than non-Porton Down veterans. With lack of information on other important factors, such as smoking or service overseas, it is not possible to attribute the small excess mortality to chemical exposures at Porton Down.

Cancer morbidity in British military veterans included in chemical warfare agent experiments at Porton Down: cohort study.

OBJECTIVE: To determine cancer morbidity in members of the armed forces who took part in tests of chemical warfare agents from 1941 to 1989. DESIGN: Historical cohort study, with cohort members followed up to December 2004. DATA SOURCE: Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. PARTICIPANTS: All veterans included in the cohort study of mortality, excluding those known to have died or been lost to follow-up before 1 January 1971 when the UK cancer registration system commenced: 17,013 male members of the UK armed forces who took part in tests (Porton Down veterans) and a similar group of 16,520 men who did not (non-Porton Down veterans). MAIN OUTCOME MEASURES: Cancer morbidity in each group of veterans; rate ratios, with 95% confidence intervals, adjusted for age group and calendar period. RESULTS: 3457 cancers were reported in the Porton Down veterans compared with 3380 cancers in the non-Porton Down veterans. While overall cancer morbidity was the same in both groups (rate ratio 1.00, 95% confidence interval 0.95 to 1.05), Porton Down veterans had higher rates of ill defined malignant neoplasms (1.12, 1.02 to 1.22), in situ neoplasms (1.45, 1.06 to 2.00), and those of uncertain or unknown behaviour (1.32, 1.01 to 1.73). CONCLUSION: Overall cancer morbidity in Porton Down veterans was no different from that in non-Porton Down veterans.

Low molecular weight chemicals, hypersensitivity, and direct toxicity: the acid anhydrides.

The acid anhydrides are a group of reactive chemicals used widely in alkyd and epoxy resins. The major hazards to health are mucosal and skin irritation and sensitisation of the respiratory tract. Most occupational asthma caused by acid anhydrides appears to be immunologically mediated. Immunological mechanisms have been proposed to explain an influenza-like syndrome and pulmonary haemorrhage, but direct toxicity may also be important in the aetiology of these conditions.

Prevention of occupational asthma.

This paper focuses on the prevention of asthma caused by exposure to sensitizing agents in the workplace. Control of exposure (primary prevention) is the most direct method of reducing the number of incident cases. Screening programmes are also necessary as a "safety net", and have value as secondary prevention, because early detection may improve long-term prognosis. It is recommended that regulatory or advisory bodies with responsibility for occupational asthma publish a guidance document on occupational asthma explaining their current concepts. Surveillance activities provide information on how common asthma is relative to other occupational lung diseases, and on the relative frequency of occurrence of asthma caused by different agents. Publication of a list of sensitizing agents would aid those with responsibility for control of exposure in the workplace. Epidemiological research on exposure-response relations is is necessary as a background to prevention. This paper recommends such studies. Immunotoxicological research also has a role in testing hypotheses that cannot be tested in human subjects. Some standardization of screening programmes in industry is desirable. A short symptoms questionnaire is economical and acceptable to workers, but there are other approaches. Finally, evaluative research on prevention measures gives information on their effectiveness and efficiency.

Occupational asthma.

Occupational asthma is a common disorder that may be caused by several hundred agents and has a variety of pathogenetic mechanisms. Level of exposure is an important risk factor, and reduction of exposure is the only certain method of prevention. Atopy and smoking are further risk factors for IgE-mediated asthma but have not been found to increase risk in forms of the disorder that have other mechanisms. The key to diagnosis is a low threshold of suspicion; several investigative procedures can be used to confirm the diagnosis. Many patients suffer from continued asthma despite cessation of exposure; early diagnosis and early removal from exposure are the most important factors for improving the long-term outcome.

Exposure-response relationships in asthma caused by tetrachlorophthalic anhydride.

Four patients with asthma caused by occupational exposure to tetrachlorophthalic anhydride (TCPA) had dust-challenge tests that used eight different levels of TCPA exposure. Measurements of TCPA in the test-cubicle air ranged from 1.3 to 961.1 micrograms/m3. The higher exposures provoked definite late or dual asthmatic responses. Smaller, but statistically significant, responses were observed at low exposures. The late asthmatic-response area had a linear relation to the logarithm of TCPA exposure, but the immediate asthmatic response was less closely related to exposure.

Specificity of the human IgE response to inhaled acid anhydrides.

Patients with work-related respiratory symptoms caused by inhaled acid anhydrides (trimellitic (TMA), phthalic (PA), tetrachlorophthalic (TCPA), and maleic anhydrides) have specific IgE antibody. The antibody is specific for a conjugate of the sensitizing anhydride (the hapten) and human serum albumin (HSA). We have investigated the specificity of the reaction to determine whether the antibody is directed against (1) the anhydride, (2) new antigenic determinants formed by conjugation of albumin with the anhydride, or (3) the complete anhydride-HSA conjugate. For the patients sensitized to TCPA and TMA, RAST inhibition studies demonstrate the anhydride-HSA conjugate to be a more effective inhibitor of RAST than the sodium salt of the anhydride or an anhydride-bovine serum albumin conjugate, whereas for those sensitized to PA, the free hapten is almost as an effective inhibitor as the conjugate. With each sera HSA conjugates of anhydrides to which the patient is not sensitized are weaker inhibitors than the sensitizing anhydride-albumin conjugate. These results provide strong evidence that for the patients sensitized to TCPA and TMA, the antibody combines with the anhydride and the spatially adjacent portion of the HSA molecule, whereas in the patients sensitized to PA, the antibody is specific for the hapten.

Pseudo-occupational asthma.

A case is reported in which a pattern of work related asthma in a record of peak expiratory flow was artefactual. The patient had pronounced morning dips, which she recorded on working days, when she made the first recording at 0700 h, but not on holiday, when she stayed in bed longer. The case emphasises the need for clear instructions to patients about peak flow records.

Stepwise health surveillance for bronchial irritability syndrome in workers at risk of occupational respiratory disease.

OBJECTIVES: Questionnaires, lung function tests, and peak flow measurements are widely used in occupational health care to screen for subjects with respiratory disease. However, the diagnostic performance of these tests is often poor. Application of these tests in a stepwise manner would presumably result in a better characterisation of subjects with respiratory disease. METHODS: Cross sectional data from workers exposed to acid anhydrides, to laboratory animals, and to flour dusts were used. Sensitivity and specificity were calculated from cross tables of different (combinations of) tests for bronchial hyperresponsiveness and bronchial irritability in the past four weeks (BIS). From sensitivity and specificity likelihood ratios were computed and change in probability of BIS was calculated. RESULTS: The prevalence of BIS was 7%, 7%, and 5%, respectively. In all groups questionnaire data provided excellent sensitivity but poor specificity, which was inherent on the broad definition of symptoms. Adding the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio yields almost perfect specificity, and peak expiratory flow (PEF) variability is intermediate in populations in which smoking induced or non-allergic respiratory diseases predominates. In occupational groups in which asthma is a problem, adding PEF measurements will optimise sensitivity and specificity in detection of BIS. The probability of BIS for subjects with a negative combined test outcome was lower than the probability before testing. Subjects with a positive combined test outcome had a probability of BIS after the tests at least three times the probability before. CONCLUSIONS: Combined testing yields better sensitivity and specificity. An advantage of combined testing is an economy in the effort to screen for subjects with BIS. Combined testing resulted in more detailed estimation of the probability of BIS.

Flour dust exposure variability in flour mills and bakeries.

As part of a longitudinal study to explore the exposure-response relationship between flour dust exposure and work-related symptoms and skin sensitivity the authors formed exposure groups and estimated various components of variability. This paper describes the between-exposure group, the between-worker and the within-worker variation of personal flour dust exposure in bakeries, flour mills and packing stations. In total 346 samples were collected in 13 exposure groups. The geometric means of the exposure groups ranged from 0.3 up to 9.0 mg m-3. Between-worker variances within exposure groupings were less than the overall between-worker component although substantial differences in exposure between workers remained in some exposure groups. Overall the largest variance component was the between-exposure group component followed by the considerably smaller between-worker and within-worker components.

Correlation between different measures of exposure in a cohort of bakery workers and flour millers.

This paper describes the relationship between continuous and 'grouped' variables for several measures of exposure in a longitudinal study of bakery workers and flour millers. Average shift and peak levels, both for dust and for flour aeroallergen were measured, duration of exposure obtained from questionnaire and cumulative exposure both for dust and for flour aeroallergen calculated. Neither for dust nor for flour aeroallergen was there a correlation between duration of exposure and intensity measures of exposure (peak and average). Moderate to good correlation existed between the various intensity measures of exposures both for dust and for flour aeroallergen. Good correlations existed between measures of exposure of dust and measures of exposure for flour aeroallergen. The degree of correlation was reflected by the fact that the number of workers changing categories depended on which measure of exposure was considered. The higher the correlation coefficient between various measures of exposure the fewer workers changed category. This information provides important information for a better understanding of the exposure-response relationship amongst bakery workers and flour millers.

Peak flow rate records in surveys: reproducibility of observers' reports.

Records of peak expiratory flow rate (PEFR), commonly used in hospital in the management of asthma, have not been evaluated as a method of identifying cases of asthma in population surveys. Four observers were asked to report on whether asthma was present or absent in 61 graphs of PEFR recorded two hourly for four weeks during surveys of working population. Agreement within individual observers was measured using a subset of 29 graphs which had been copied and distributed at random among the set of 61; agreement was good, from 90% in one observer to 100% in two. Agreement between observers was measured on the basis of all 61 graphs. Agreement occurred between all four observers in 69% of graphs, between at least three out of four in 97%, and, when pairs of observers were examined, between 72% and 93% of graphs. Graphs assessed as showing asthma demonstrated more within day PEFR variability (expressed as the number of days in which the difference between maximum and minimum readings was at least 15%) than graphs assessed as not showing asthma. Some graphs with little within day variability were assessed as showing asthma, apparently because they demonstrated between day PEFR variability.