The aim of the work described in this thesis was to develop a reliable method for retrospective assessment of occupational exposure, for individual workers, to substances hazardous to health. A review of existing methods for reconstructing exposure has shown a diverse range of approaches, partly dictated by the availability of measurement records and other documentation about work activities. These methods show little evidence of a coherent theoretical basis for exposure assessment. Progress has been made in defining a theory of exposure to hazardous substances and in elaborating this for substances where the main route of exposure is by inhalation. A new metric for exposure assessment, i.e. uptake, is proposed. For inhalation this corresponds to the cumulative amount of material inhaled during the exposure period, e.g. for a dust this would correspond to the time integral of the product of exposure level (i.e. concentration) and breathing rate. Analogous definitions are provided for dermal and ingestion uptake, and total uptake as the sum of these individual measures. It is argued that uptake should provide the best metric for reconstructing past exposure. For inhalation exposure several stages have been identified linking emission of hazardous substances from sources to inhalation of the substance by an individual worker. Emission from sources into the work environment has been divided into three parts (i.e. intrinsic emission, plus the effects of handling and local controls), which are assumed to be independent of each other. It is further assumed that the total emission from a source is determined by the product of these terms.

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Occupational exposure of pesticides occurs via inhalation through the lungs or by absorption through the skin. The assessment of the possible importance of these extrahepatic tissues in the hydrolysis of pesticides is important. Although the liver has been shown to be the most metabolically active tissue, both the skin and lung have the ability to metabolise pesticides. Therefore, the possibility exists that pesticides which are absorbed through the lung and skin may undergo first pass metabolism in these tissues. In the study, the esterase enzymes responsible for the hydrolysis and subsequent detoxification of a number of pesticide substrates were identified and quantified. Esterases which hydrolysed the pesticides fluazifop-butyl and carbaryl and phenylacetate, a marker substrate for esterase activity, were found to be distributed in the microsomal fraction of the liver and lung and in the blood. In vitro studies in the rat show that lung, skin and plasma have an important role to play in the first pass metabolism of the pesticides fluazifop-butyl and carbaryl. In paraoxon hydrolysis, the plasma plays an important role in first pass metabolism, whereas the lung and skin have little effect. With the use of inhibitors and inducers these esterase enzymes were characterised as `A' or `B' esterases. Fluazifop-butyl and carbaryl were hydrolysed by carboxylesterase, a `B' esterase, whereas paraoxon was hydrolysed by paraoxonase, an `A' esterase. Phenylacetate was found to be hydrolysed by both `A' and `B' esterases. Parallel studies were carried out in human liver and blood to establish whether the rat was an appropriate model for study of the detoxification of pesticides by esterases. Studies have shown that there is considerable similarity in the nature of human and rat esterase enzymes, although there are significant differences in absolute activities.

Welders and caulker/burners are usually exposed to heavy clouds of fumes. These fumes contain some gases and particulates which are potentially harmful. There have been several surveys of the health of welders since 1936. These studies demonstrated an association between exposure to fumes and respiratory symptoms. However, no long term effect of fumes on respiratory function has been established. The gases and particulates in the fumes from welding and caulking/burning are very small in size and on this account are capable of reaching the small airways in the periphery of the lung. If welding fumes are harmful to the lung small airway dysfunction should be present in the younger workers. In view of this, in the present study relatively young men were examined and tests specific to small airway function were used. The subjects for this study were male Caucasian workers aged 18 - 47 years, mean age 31.5 years. The target sample comprised 181 welders and 151 caulker/burners and the control sample comprised 181 other tradesmen. The two samples were selected from the same yard. Anthropometry, respiratory symptom and occupational questionnaires, cough frequency questions, forced spirometry, single breath nitrogen test, transfer factor, and an exercise test were performed. The results were submitted to multiple regression analysis. The target workers were compared with the control subjects. Comparisons were also made within the groups of welders and caulker/burners separately. A subsample of the whole selected subjects (age 20 - 25 years) was examined separately to investigate the early effects of fumes on the lung of exposed young workers. In the whole population, compared with the controls, the welders and caulker/burners were found to have significantly higher prevalence of wheeze symptom, and fume exposure interacted with age to increase breathlessness on exertion in the older subjects. In the very young workers (age 20- 25 years) chronic cough and phlegm (chronic bronchitis, MRC) was significantly higher among the target workers compared with the controls. In the group of welders smoking interacted with fumes to increase wheeze in the workers who smoked while increased fume exposure in the older subjects was associated with increased breathlessness on exertion. In the whole population the mean values of closing volume (CV%) and closing capacity (CC%) were significantly higher in the target workers compared with the controls. This effect was independent of age and smoking which were also important. In the subsample of the very young workers similar effects were found, and in addition the mean value of the residual volume (RV%) in the target group was significantly higher than that in the control group. In the whole population fume exposure enhanced the deterioration with age in forced expiratory volume (FEV1) and forced vital capacity (FVC) significantly more in the target workers than in the control subjects. These indices were not affected by exposure in the very young workers. Amongst the group of welders, increased levels of exposure to fumes (duration and intensity) enhanced the deterioration with age in CV%, CC%, breathlessness on exertion and Tlco. High exposure was also associated with decreased Kco in the workers who smoked. Amongst the caulker/burners, increased levels of exposure to fumes enhanced the deterioration with age in CV%, CC%, slope of phase III (SLIII), nitrogen difference index (N2 Diff) and RV%. The findings of the present study are evidence that high levels of fumes from welding and burning or other factors related to these trades, cause long term impairment of lung function of shipyard welders and caulker/burners.

Hair has a number of advantages over more conventional sample types, such as serum, whole blood and urine, as an indicator of the intake and exposure to trace elements. While the analysis of these conventional sample types can only be used as a measure of recent exposure, hair, in contrast, can provide an historical record of exposure episodes. Furthermore the levels of trace elements in hair are higher than in blood and as a result small changes in intake are magnified. In addition, the collection of hair samples is non-invasive and the samples are easy to store. However, the difficulty in differentiating surface bound contamination from trace elements incorporated into the hair matrix complicates the interpretation of the hair analysis results. A review of the literature showed that a variety of washing procedures to remove external contamination have been proposed but as yet no standardised procedures are available. In this study, methods for the pretreatment and determination of antimony, arsenic, cadmium, chromium, lead, mercury and selenium in human hair by ICP-MS were developed. Chemical speciation of mercury and methyl mercury in hair was also achieved using LC-ICP-MS. For the digestion of hair samples the optimum method for these elements was found to be a digestion mixture of nitric acid and hydrogen peroxide. Certified reference materials CRM 397 and CRM 07601 were digested using this method and the values obtained were seen to be in good agreement with the certified values. Investigations of various washing procedures to remove external contaminants showed that in unexposed hair samples cadmium, lead and mercury were significantly removed from hair using a 0.1M HCl wash, with 87%, 73% and 5% respectively being washed off. Whilst the removal of antimony, arsenic and chromium from unexposed hair was more efficient with 1% v/v sodium lauryl sulphate, with 43%, 40% and 13% of each element respectively being washed off. Selenium could not be removed from the hair by any of the washing methods studied. Experiments with simulated sweat spiked with each of the elements showed that exogenously bound chromium, cadmium and lead could be removed after washing with 0.1M HC1. In contrast, antimony, arsenic, selenium and mercury were irreversibly bound and could not be removed with any of the washing solutions investigated. Using a LC-ICP-MS system it was possible to separate inorganic mercury and methyl mercury in hair, without any modifications to the existing instrumentation. The results showed that in order to determine methyl mercury the sample had to be cold digested in 2: 1 HNO3: H202 and that a minimum of 0.1g of hair is required. Using this method of analysis it was seen that with spiked simulated sweat solutions exogenously bound methyl mercury could be removed from hair after washing with 0.1M HCI, whereas the inorganic mercury was irreversibly bound to the hair. It was also found that inorganic mercury was the major mercury species in hair from dental subjects. The results of a six week selenium supplementation study of 29 subjects showed an increase in hair selenium levels of 19%, confirming that hair concentrations of selenium can give a good reflection of selenium status in the body. A control group of 40 unexposed samples were analysed to determine normal levels of antimony, arsenic, cadmium, chromium, lead, mercury and selenium in human hair. Occupational studies were then carried out and the data obtained from these studies showed a significant increase in the elements of exposure. Hair samples from dental workers (n = 43) showed a mean mercury level of 813 ng g-1 compared to a control value of 287 ng g-1; hair samples from semiconductor workers (n = 24) showed a mean arsenic level of 208 ng g'1 compared to a control value of 34 ng g'1; hair samples from chromium platers (n = 7? showed a mean chromium level of 2201 ng g-1 compared to a control value of 985 ng g-1 ; and hair samples from lead foundry workers (n = 13) showed a mean lead level of 124337 ng g-1 compared to a control value of 1030 ng g-1. The lead levels in the foundry workers' hair samples were reduced by 94% after washing with 0. IM HCl from 124 000 to 7440 ng g-1, which was still above the normal group mean hair lead level of 1030 ng g-1.