Prediction of outcome after paraquat poisoning by measurement of the plasma paraquat concentration.

BACKGROUND: Paraquat is a herbicide with a good occupational safety record, but a high mortality after intentional ingestion that has proved refractory to treatment. For nearly three decades paraquat concentration-time data have been used to predict the outcome following ingestion. However, none of the published methods has been independently or prospectively validated. We aimed to use prospectively collected data to test the published predictive methods and to determine if any is superior. METHODS: Plasma paraquat concentrations were measured on admission for 451 patients in 10 hospitals in Sri Lanka as part of large prospective cohort study. All deaths in hospital were recorded; patients surviving to hospital discharge were followed up after 3 months to detect delayed deaths. Five prediction methods that are based on paraquat concentration-time data were then evaluated in all eligible patients. RESULTS: All methods showed comparable performance within their range of application. For example, between 4- and 24-h prediction of prognosis was most variable between Sawada and Proudfoot methods but these differences were relatively small [specificity 0.96 (95% CI: 0.90-0.99) vs. 0.89 (0.82-0.95); sensitivity 0.57 vs. 0.79, positive and negative likelihood ratios 14.8 vs. 7.40 and 0.44 vs. 0.23 and positive predictive values 0.96 vs. 0.92, respectively]. CONCLUSION: All five published methods were better at predicting death than survival. These predictions may also serve as tools to identify patients who need treatment and for some assessment to be made of new treatments that are trialled without a control group.

Study of two cohorts of workers exposed to methyl methacrylate in acrylic sheet production.

OBJECTIVES: To study mortality among 4324 workers at two United Kingdom factories, Darwen, Lancashire and Wilton, Cleveland, producing polymethyl methacrylate (PMMA) sheet. The Darwen factory is still active, but the Wilton one was closed in 1970. Also, to investigate patterns of mortality after exposure to methyl methacrylate; in particular, mortality from colon and rectal cancer. METHODS: All male employees at the Darwen factory with a record of employment in 1949-88 and all men ever employed at the Wilton factory (1949-70) were investigated. The vital status of both cohorts was ascertained on 31 December 1995. The exposure of 1526 subjects at the Darwen plant who were engaged from 1949 onwards could be characterised. The mean duration of exposure was 7.6 years at 13.2 ppm (8 hour time weighted average), although exposures in some work groups were as high as 100 ppm. It was not possible to calculate the cumulative exposure of workers first employed at the Darwen plant before 1949 or workers at the Wilton factory. RESULTS: In the Darwen cohort, 622 deaths were identified and a further 700 deaths in the Wilton cohort. Mortalities for the cohort were compared with national and local rates and expressed as standardised mortality ratios (SMRs). In the subcohort of Darwen workers with more than minimal exposure to MMA, reduced mortalities compared with national and local rates, were found for all causes (SMR 94), and colorectal cancer (SMR 92), but mortality from all cancers was slightly increased (SMR 104). No relations were found with cumulative exposure to MMA. In the subcohort of Wilton workers, mortality from all causes of death was significantly reduced (SMR 89), but mortality from all cancers (SMR 103) and colorectal cancer (SMR 124) were increased. The excess of colorectal cancer was confined to employees with less than 1 year of employment. CONCLUSION: The study provided no clear evidence that employment at the factories or exposure to MMA had adversely affected the mortalities of workers.

Prevalence of solar damage and actinic keratosis in a Merseyside population.

This study examines the prevalence of sun-related damage to the skin in a caucasian population in north-west England. The importance of constitutional factors (complexion, skin type and age) as well as environmental and occupational exposures for the development of actinic keratosis (AK) and skin cancers was assessed in people over 40 years of age attending outpatient clinics (non-dermatology) at four centres in north-west England (Mersey region). Nine hundred and sixty-eight volunteers (531 men and 437 women) were recruited. The overall prevalence of AK was 15.4% in men and 5.9% in women. The prevalence was strongly related to age in both sexes, being 34.1% and 18.2%, respectively, in men and women aged 70 years and above, and was most strongly related to two objective signs of sun exposure, namely degree of solar elastosis and presence of solar lentigines. The prevalence of AK was higher in subjects with red hair and freckles, particularly women. There was no evidence of an increased prevalence of AK in relation to any occupation. There was a high prevalence of seborrhoeic keratosis and viral warts in both sexes, which was age-related in the case of seborrhoeic keratosis. Ten cases of basal cell carcinoma, eight cases of Bowen's disease and one case of malignant melanoma were identified. This study shows that the sun exposure received in 'normal' life in England is sufficient to cause potentially malignant skin damage in a significant proportion of the population.

An assessment of fertility in male workers exposed to molinate.

Molinate is a thiocarbamate herbicide used for weed control in rice fields. Since the late 1970s, findings from reproductive toxicology studies of rats have led to concern that molinate might affect human male fertility. Semen samples were collected from 272 formulation and production workers at three US plants. The samples were collected at the end of four alternate monitoring periods of either high or low exposure to molinate. In addition, 222 married workers provided reproductive-history information. Workers' mean exposures to molinate during the monitoring periods ranged from 12.7 micrograms/m3 to 210.9 micrograms/m3. There was no evidence that sperm and serum hormone levels were related to exposure to molinate before the study or exposure during the four monitoring periods. There was also no evidence of a molinate exposure-related effect on the ratio of observed to expected births.

Study to evaluate the effectiveness of stress management workshops on response to general and occupational measures of stress.

This study was designed to evaluate the effectiveness of stress management training workshops within Zeneca Pharmaceuticals. The study was of cross-sectional design, comparing groups of workshop attendees and non-attendees. In addition, self-rated well-being scores of attendees were compared with results obtained pre-workshop and 2-3 months after the workshop. Employees participating in the study were drawn from the Manufacturing, Research and Development, Sales and Marketing sites of Zeneca Pharmaceuticals located in Cheshire, United Kingdom. Three hundred and ninety persons who had participated in stress management workshops since 1988 were matched for age, gender and department with an equal number of employees who had not attended stress management workshops. Outcome measures included self-rated well-being (as measured by the 30-question General Health Questionnaire), knowledge of company guidance on the management of stress in staff, and an assessment of coping strategies. Subjects who had not attended a stress management workshop were much more likely to have a poor understanding of the principles of management of stress in staff [odds ratio (OR) = 8.3; 95% confidence interval (CI) = 3.3-21.3] and more likely to have poor coping skills (OR = 2.8; CI = 1.3-6.1). However, mean scores for the two measures were similar in attendees and non-attendees. Self-rating of current well-being was strongly associated with the life-events score, but not related to workshop attendance. The study indicates that stress management training workshops reduce the prevalence of employees with a poor understanding of the principles of the management of stress in staff and with poor coping strategies. An improvement in the self-rated well-being observed shortly after the workshop was not sustained.

Molinate: rodent reproductive toxicity and its relevance to humans--a review.

Molinate is a thiocarbamate herbicide used on rice. During the evaluation of the compound for regulatory compliance, an adverse effect on male reproduction in rats was observed. This led to extensive investigations in rats, mice, rabbits, dogs, monkeys, and humans, resulting in a description of the cause of the effect and establishing an empirical case for rodent specificity. More recent investigations have also shown an effect on the ovaries in rodents. A series of investigations into the mechanism of action to support the view that the effect was specific to rodents has been concluded. The results from this investigation are drawn together and show that the mode of action is via a metabolite, the sulfoxide, which is primarily found in rodents, and that the lesion in both rodent sexes is elicited via inhibition of the enzyme neutral cholesterol ester hydrolase, resulting in interference with mobilization of cholesterol from high-density lipoprotein, a path specific to rodents. Thus, the mechanism of action is such that the effect cannot be elicited in other species including humans.

Mortality of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base.

OBJECTIVE: To study mortality among 1785 employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom. Also, to investigate patterns of mortality after exposure to methylene chloride; in particular, mortality from liver and biliary tract cancer, lung cancer, pancreatic cancer, and cardiovascular disease. SUBJECTS AND METHODS: All male employees with a record of employment at the film factory in 1946-88. A total of 1473 subjects worked in jobs that entailed exposure to methylene chloride. The mean duration of exposure was nine years at 19 ppm (eight hour time weighted average). RESULTS: In the cohort, 334 deaths were identified up to 31 December 1994. Mortalities for the cohort were compared with national and local rates and expressed as standardised mortality ratios (SMR). In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and the principal cancer sites of interest. The significantly reduced lung cancer mortalities in exposed workers (SMR 48) seemed to reflect the restrictions on smoking at the workplace. In contrast, mortality from ischaemic heart disease in exposed workers, although lower than national rates (SMR 92), was slightly increased compared with local rates. However, mortality from ischaemic heart disease was lower in active employees (SMR 83) where a direct effect of exposure to methylene chloride should be concentrated. No in service mortality due to ischaemic heart disease was found in workers with the highest cumulative exposure (> or = 800 ppm-years). CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers.

Hepatic function in workers occupationally exposed to carbon tetrachloride.

OBJECTIVES: To identify any differences in hepatic function between workers exposed to carbon tetrachloride and controls, and to identify the best variable with which to examine any effects. METHODS: In a cross sectional study of hepatic function in workers occupationally exposed to carbon tetrachloride, 135 exposed employees were compared with 276 non-exposed controls. The exposed group was taken from three sites in the north west of England and the control group included non-exposed workers from one of these sites and another site located nearby. Demographic and alcohol consumption data were collected from both groups by questionnaire. Each member of the study group was allotted a notional estimated exposure to carbon tetrachloride, calculated from historic personal monitoring data and job category. A fasting sample of blood was taken from all participants and analysed for a variety of biochemical and haematological variables. The techniques of univariate and multivariate analysis of variance were used to investigate the effect on biochemical and haematological indices of a range of factors. RESULTS: Multivariate analysis of variance of four core liver function variables, alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase, showed a significant difference between exposed and non-exposed workers. The univariate analyses identified increases in only alkaline phosphatase and gamma-glutamyl transferase within the exposed group and these did not show a significant dose-response relation. Univariate analysis of variance did show effects of alcohol and age on several variables. Significant differences between exposed and control groups for three haematological variables, haemoglobin, packed cell volume, and red blood count, were thought not to be due to the effects of exposure. Clinical review of exposed subjects with abnormal results did not show clinically evident disease that could have been associated with exposure to carbon tetrachloride. Also, a follow up study conducted three years after the cross sectional study at the site with highest exposures to carbon tetrachloride showed no evidence of any further changes in liver function variables. CONCLUSIONS: The most sensitive statistical methods have shown significant differences in the liver function variables measured between people exposed to carbon tetrachloride and the control group. The interpretation of the data collected was that these differences may be due to exposure to carbon tetrachloride but this was not clearly shown. Furthermore, the changes found have not given rise to any clinical disease.

Allergy to laboratory animals: a follow up study of its incidence and of the influence of atopy and pre-existing sensitisation on its development.

OBJECTIVES: To investigate the incidence of allergy to laboratory animals (ALA) during the first two years of employment, and to study the effect on ALA of atopy and sensitisation. METHODS: A follow up prospective study of ALA at the Zeneca (formerly ICI) Research Laboratories. RESULTS: The incidence of the disease during the first year of employment has remained at about 10% since the mid-1980s. This compares with an incidence of 37% in the early 1980s. The reduction in incidence and its maintenance at a lower level is thought to be due to the introduction and management of improved engineering controls, working practices, and educational programmes designed to reduce exposure to allergens from laboratory animals. The underlying incidence of immunological sensitisation to animals (the presence of immunoglobulin E (IgE) antibodies to animal allergens) is much higher (40% after one and 53% after two years of exposure). Both atopic diathesis and presensitisation to laboratory animals increased the likelihood that a person would develop ALA. CONCLUSION: Neither factor predicted the disease accurately so their use should be restricted to the identification of people who may be more susceptible to the development of ALA (and thus who may need to pay particular attention to the use of personal protective equipment) rather than to their exclusion.

Better quality studies through review of protocols.

The importance of a protocol is well recognized by scientists whose work is governed by good laboratory practices. Epidemiologists have used protocols for many years but have not always reaped the full benefits. Until relatively recently, there has been little consensus among epidemiologists about what constitutes a good protocol and, consequently, expectations of the pre-study review process may not be fulfilled. This paper examines some of the benefits to be derived from a good protocol and the importance of prestudy review. Our experience suggests that peer review cannot substitute for a competent principal investigator supported by a strong study management team. If such a study management team exists, the most important contribution of the external peer reviewer should be to ensure the impartiality of the study.

Association between exposure to a stenching agent in a herbicide packing plant and the occurrence of headache and lethargy.

This study quantifies the relationship between subjective complaints of symptoms and certain work activities and exposures in a plant where herbicide is packed. Data relating to symptoms were collected from 27 subjects (20 men and 7 women) on a daily basis with the use of a questionnaire. In addition, data were collected relating to work activity and exposure to the stenching agent added to the herbicide, atmospheric levels of which were measured with personal monitoring, on a daily basis. Although associations were found between the occurrence of lethargy and certain factors of job history, there was no significant association with exposure to the stenching agent as measured by personal monitoring during the study.

The calibration of the second primary international reference preparation for thromboplastin (thromboplastin, human, plain, coded BCT/253).

An international collaborative exercise has been undertaken to calibrate a replacement for the first WHO primary international reference preparation (IRP) for thromboplastin. The replacement preparation is a lyophilised batch of British Comparative Thromboplastin (BCT/253, human plain) for use in the Quick prothrombin time test. Seventeen centres participated. The experimental design, calibration model and statistical analysis were based on the recommended WHO procedure. As a result of this calibration exercise an International Sensitivity Index (ISI) of 1.1 has been assigned to the preparation by WHO and it has been officially recognised as the second primary IRP for thromboplastin. The calibration of BCT/253 is an essential link in a new hierarchical structure for the standardisation of the prothrombin time. The aim is to provide a uniform international system of reporting prothrombin time results using International Normalised Ratios (INR) derived from the ISI of individual thromboplastins.

Insurance and the disabled.

The provision of life insurance for the disabled has been investigated to determine the extent to which the perceived disadvantage expressed by some disabled groups was real and, if real, justified. Life cover for a particular disability is likely to be offered only by the few companies with experience of it; however, the ratings charged appear usually to be a fair reflection of the limited and often poor information available. The response of organizations for the disabled to this problem has been reviewed, and possible strategies to enable the disabled to obtain insurance are suggested.

The bleeding time: current practice in the UK.

A questionnaire survey of current practice in the bleeding time test has been undertaken by the UK External Quality Assessment Scheme in blood coagulation. Completed returns have been received from 358 centres. Most centres (88.5%) perform bleeding times and of these the Ivy test is the most commonly performed. Only 13.6% perform the Duke method. Templates are used to control the procedure by approximately half of the hospitals. There is considerable variability in the type and depth of incision and interpretation of the endpoint. The upper limit of normality not unexpectedly differs considerably between the centres with both Ivy and Duke methods. The use of a commercial template method, 'Simplate', provides a measure of agreement amongst the group of hospitals using this instrument but it remains to be established whether this is the most reliable procedure. In the interim, gross discrepancies in technique or interpretation should be corrected in the light of the findings of the survey.