HEALTH EFFECTS OF WELDING AND CUTTING FUME - AN UPDATE

Gary M. Liss, MD, MS, FRCPC
Ontario Ministry of Labour
Final Report December 1996

SUMMARY

In 1985, this author prepared a document on the Health Effects of Welding and Cutting Fume, and in 1995, was asked by the Occupational Disease Panel to update the document. As in the initial review, this report is limited to effects associated with the gaseous and particulate components of the fume. For each outcome, recent findings are summarized and consistency was sought with the evidence noted in the earlier report.

Welding is an important occupational activity, in part because from 0.2 to 2.0% of the working population in industrialized countries has been reported to be engaged in welding. Although there are a vast number of processes, it has been estimated that shielded metal arc welding (SMAW, also known as manual metal arc welding, MMAW) and gas metal arc welding (GMAW or metal inert gas welding) applied to mild steel (MS), stainless steel (SS) and aluminum account for combinations practised by 70% of welders. The welding environment is very complex, with the presence of numerous gaseous and particulate components. The consumable is the major source of fume, although exposures extraneous to the process itself can be generated, such as decomposition products from chlorinated hydrocarbons or metal coatings. As a result of the multiple exposures, in general it is not possible to attribute health effects to specific fume contaminants or welding processes.

Welders continue to suffer both acute and chronic health problems that appear to be associated with work. With respect to acute effects, as found prior to 1985, acute intoxications continue to be observed, consisting mostly of case reports of lead intoxication, and upper and lower respiratory tract inhalation (bronchitis, pneumonitis) which may be process- or metal-dependent (cadmium, decomposed chlorinated hydrocarbons, coatings on metal). Severe cases of pneumonitis from inhalation of welding fume, such as that due to cadmium, may cause permanent sequelae or fatalities. The reports of increased mortality among welders due to pneumonia documented in the early time period have also been confirmed since 1985, and prompted one group of investigators (Coggon et al, 1994) to conclude that "there are strong grounds for the classification of lobar pneumonia as an occupational disease in welders". Metal fume fever (MFF) is an acute febrile illness of short duration due to inhalation of freshly generated fume that affects important proportions of welders (up to 30% in some estimates) and results from the inhalation of freshly formed oxides, most commonly that of zinc. The cause is not known but the syndrome resolves leaving no apparent chronic disorder. A new finding which was reported by Blanc et al (1993) suggested that various cytokines released from pulmonary cells may be involved in the pathogenesis of MFF.

Compared to the knowledge base in 1985, there is now evidence for acute (short-term) changes in pulmonary function among welders, that appear to be related to exposure (that is, present in groups with higher exposure or the absence of ventilation systems). A case of asthma was recently described by Vandenplas et al (1995) associated with GMAW on MS, which was confirmed on inhalation challenge with both late and dual reactions. Hendrick (1996) reported (in abstract form) that there was increased nonspecific methacholine reactivity among welders. Occupational asthma was also reported more frequently among welders than among the working population in general, in the Surveillance of Work-Related and Occupational Respiratory Diseases (SWORD) scheme in the United Kingdom (Meredith et al, 1991). The incidence of asthma among welders in one prospective study (Wang et al, 1994) was similar among MS vs SS welders. However, because the incidence of asthma observed in this study was not much different than that estimated in the general population, the evidence for an association with asthma cannot be considered conclusive.

For the studies of non-malignant respiratory diseases (symptoms, pulmonary function) and lung cancer, the quality of the studies was rated independently by two reviewers. With respect to chronic health effects, given the respirable nature of welding fume, chronic non-malignant respiratory disease continues to be an important focus of attention. Fourteen new studies were identified. Longitudinal studies have now been reported (as recommended in 1985); thus, the available studies are not all cross-sectional with the inherent weaknesses of this study design although the presence of confounders (especially smoking) still plagues the interpretation of these studies. Some but not all studies continue to demonstrate an increased prevalence of symptoms (chronic bronchitis as well as other symptoms) among welders compared to referents. While non-smokers were affected in some studies, there was evidence for an interaction with smoking in those reports where examined, with greater effects seen among smokers. Welders developed some respiratory symptoms (although not chronic bronchitis) more frequently than controls in 2 of 3 longitudinal studies. One study (Groth, 1989) found dose-response relationships for pulmonary symptoms among both smokers and non-smokers. Similarly, there is evidence from some but not all of the recent studies for enhanced deterioration of pulmonary function among welders compared to referents, involving the small airways somewhat more frequently than the large airways, and again with greater effects observed among smokers in some studies. These changes were not seen consistently across studies, however. In one study, obstructive changes were seen more frequently among older smoking welders than controls but restrictive changes were more prevalent among non-smoking welders. Enhanced deterioration of some pulmonary function measures was seen in all 3 longitudinal studies. Summarizing this issue, Wanders et al (1992) examined "medical wastage" among shipyard welders and controls (shipwrights and engine fitters at the same shipyard) as part of a 40-year cohort study. Medical wastage was defined as leaving for medical reasons under the Disability Act, invalidity pensions, death, and voluntary discharge for medical reasons. The only diagnostic category of medical wastage that was significantly different between the two groups was for non-malignant respiratory disease (greater among welders), with an adjusted incidence density ratio of 4.2 (95% confidence interval [CI] 2.4-7.4). The authors concluded that it underscores the "need to reduce the large excess of respiratory diseases among shipyard welders". Overall, the evidence is somewhat better than that existing a decade ago.

As was found prior to 1985, there continue to be case reports documenting pulmonary fibrosis among welders, but these have now been shown to occur in the absence of silicosis. However, there are still no studies of the incidence of fibrosis among welders. Siderosis, a pneumoconiosis due to pulmonary deposition of iron particles, appears as nodular radiodensities on chest x-ray. Siderosis itself is usually considered to be benign, without fibrosis, and if fibrosis is present, is considered to be due to exposure to other dusts, such as crystalline silica. However, one epidemiological study by Funahashi et al (1988) involved histological examination of lung tissue obtained from 10 symptomatic welders with abnormal radiographs. They found evidence of interstitial pulmonary fibrosis that was moderate to pronounced in five and this did not appear to be related to co-existing silicosis.

With respect to nonrespiratory chronic effects, an increased prevalence of neuropsychiatric symptoms has been reported among welders, but confirmation with objective neuropsychological tests is required. Most of the new studies of renal function continue to provide little evidence for renal function abnormalities among welders. However, a recent report by Nuyts et al (1995) from Belgium found an increased risk of chronic renal failure associated with exposure to welding fumes (odds ratio (OR) 2.1, 95% CI 1.1-4.0), but a dose-response relationship was not demonstrated. Some but not most studies of semen quality found a deterioration among welders. However, the studies suffer from weaknesses in methodology including low response rate and possible recall bias. There is limited evidence that the risk of Wilms' tumour is increased among the offspring of welders.

The recent in vitro studies continue to show that SS fume (particularly MMA/SS) is mutagenic and the activity correlated with the hexavalent chromium content, while MS fume demonstrated much less activity. New findings that were not found in 1985 are provided by the cytogenicity studies examining lymphocytes of welders. These studies continue to show no increases in sister chromatid exchanges among welders; however, several reports demonstrated genotoxic effects on lymphocytes of MMA/SS welders (who are most intensely exposed to chromium), consisting of chromosomal aberrations and DNA-protein cross-linking. The implications of these markers of genotoxicity for disease is uncertain at present.

With respect to cancer, associations with several types of non-respiratory cancer have been reported but there is little evidence that these findings are related to time since first exposure or to duration of employment, and will need to be confirmed.

Given the respirable nature of the fume, and the presence in welding fume of metals known or suspected to be carcinogenic in other settings, attention has naturally been drawn to assessing the possible risk of lung cancer in welders. There is no experimental evidence documenting the carcinogenicity of welding fume. Three possible explanations for the excess of lung cancer among welders discussed in the past included that it may be due to long-term MS welding of any type; that MS welding may involve little or no risk but certain welding processes, in particular SS welding, constitute a "hot spot" with a higher risk of lung cancer; or finally, that the increased risk may be due to the confounding effects of smoking, and possibly other carcinogens such as asbestos. Most of the epidemiological studies reported during 1985 or after, consistent with those reported previously, continue to document a small to moderate (about 30-40%) increase in lung cancer risk among welders. However, the findings are not consistent. The large (European) study conducted by the International Agency for Research on Cancer (IARC; Simonato et al, 1991) showed an overall increase in lung cancer mortality of 34%. However, a moderately large, well-conducted study of U.S. nonshipyard MS welders by Steenland et al (1991) found no excess (SMR 107 among welders, with SMR 117 among the comparison group of nonwelders), no trend with duration of employment, and rate ratios less than 1 on internal comparisons (0.90, 95% CI 0.60-1.36 for welders overall; 0.66 (0.33-1.30) for welding 10-20 years; and 0.65 (0.29-1.42) for welding greater than 20 years). This study was ranked as the best in quality, and was probably the one with the least potential for exposure of subjects to asbestos.

The studies of SS welders have been limited by small population size, and other than one very small study from Sweden by Sjogren et al (1987), have not shown increases in lung cancer mortality that are greater than those among MS welders in the same cohorts. Lung cancer risk among SS welders in the IARC study was not related to cumulative exposure. Thus, although it is known that there is exposure to hexavalent chromium in this group, that welders absorb hexavalent chromium, that SS welding fume is mutagenic, and that this exposure is documented to cause increased risks for lung cancer in other industries, the evidence for SS welding to date as a cause of lung cancer is unclear. Future reports may clarify this.

With respect to confounding exposures, there is evidence from a number of studies that welders are exposed to asbestos based on finding mesotheliomas in these cohorts (especially at shipyards). Of the studies providing data on smoking prevalence, there is evidence that welders smoked more than the general population in the U.S., Sweden, France, and Norway, and smoked more than internal controls in a German study. However, these differences in smoking prevalence are unlikely to explain more than a 20% increase in risk.

IARC (1990) concluded that there is inadequate evidence for the carcinogenicity of welding fumes and gases in animals and limited evidence in humans, with a classification of Group 2B (possibly carcinogenic to humans), which means "a positive association was found for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence". Given the evidence for confounding exposures, this would appear to be the case. In a recent case-control study by Jöckel et al (1994), the OR for lung cancer among welders was reduced (from 1.5 to 1.2) when adjusted for asbestos. In order to clarify this issue, case-control studies within the existing cohort studies should be undertaken, in order to examine the association of lung cancer with welding, including detailed exposure regarding MS vs SS, while controlling for smoking and asbestos.

Taken as a whole, there continues to be evidence that exposure to welding fumes and gases that existed under past and perhaps current conditions is associated with certain acute and chronic health problems among welders including relatively common conditions such as pneumonia, metal fume fever, non-malignant respiratory disease, and possibly lung cancer and other conditions. A number of new outcomes have been observed which had not been described a decade ago.

DEFINITIONS OF SOME TERMS IN THE REPORT

Welding is a process for joining metals rendered liquid by heating, by pressure, or both. Fusion welding, which includes gas and electric arc welding, involves heating the metals to a suitable temperature. In arc welding, the metal temperature is around 4000 when workpieces fuse together, although the arc temperature is much higher. The various welding processes will not be described here. However, Stern (1983a) has pointed out that two major technologies (shielded metal arc welding using stick electrodes and gas metal arc welding using continuous wire) applied to mild steel, stainless steel and aluminum account for combinations practised by 70% of welders.

Cutting or scarfing may involve cutting slab steel, removing gates and risers on castings, or gouging out defective metal in castings. Gates are the end of the runner in a mold where molten metal enters the casting or mold cavity. Risers are the reservoirs of molten metal provided to compensate for the contraction of the casting as it solidifies. In gouging, a strip of surface metal is removed but the metal is not cut through. Carbon arc cutting is an arc cutting process in which metals are severed by melting them with the heat of an arc between a carbon electrode and the base metal. In oxygas cutting, the metal is heated by a flame and a jet of pure oxygen is directed to the point of cutting, and moved along the line to be cut. Cutting differs from welding in that only one piece of metal may be involved and temperatures are somewhat lower than in welding.

Burning is the removal of surface materials, especially paint and is also improperly used to describe the process of cutting. Lead welding, often called "lead burning", is the fusion welding of lead. The heat required for lead welding is much lower than that for welding cast iron and steel.

Brazing can be defined as a technique for joining metals using a filler metal with melting point greater than 427 C (800 F) and is thus differentiated from soldering which uses filler metal or solder with a melting point less than 427 C. The processes differ from arc welding in that the filler metal is flame or contact melted rather than melted by an electric arc.

FEF_25-75 is the forced expiratory flow between the 25% and 75% of the forced vital capacity (FVC), also known as the maximum mid-expiratory flow (MMF). This is a small airway test, largely determined by the later, effort-independent part of the forced expiratory manoeuvre.

FEF₇₅ (also known as MEF_{25% FVC}) is the flow when 75% of FVC has been expired (that is, 25% of FVC left). Similarly, FEF₅₀or MEF_50%FVC is the flow when 50% of the FVC remains to be expired. These flow rates are also reduced by narrowing of the smaller lung airways.

Abbreviations for Processes

ABBREVIATIONS USED IN THE DOCUMENT

BACKGROUND

In 1985, this writer prepared a document "The Health Effects of Welding and Cutting Fume" (Liss, 1985). The Executive Summary of the document is reproduced here as Appendix 1. In March 1995, this author received a request from the Occupational Disease Panel (ODP) to update the Health Effects Document. Since it had been 10 years, it seemed timely to examine what had been published during the past decade. Preparation of this report commenced in May of this year and was completed in November 1995. This final version of December 1996 incorporates minor revisions to incorporate comments of the peer reviewers.

Terms of Reference

This review of the health effects of welding, as in the first document, is limited to the gaseous and particulate components of the fume. It should be noted that welders may also suffer an important burden of illness associated with exposure to physical agents including noise, burns, eye injuries including "arc eye"/ ultraviolet radiation, electric shock, as well as ergonomic and other musculoskeletal problems. These aspects have been reviewed elsewhere (Villaume et al. 1979; Tinkler and Graville, 1983; Zakhari et al 1983, and others) and are not considered here.

The overall approach taken is to examine the associations between health effects and welding and cutting fume exposure reported in the past 10 years. For each outcome, a brief summary is provided of what was known 10 years ago but the individual references from the earlier document are not reviewed, and then the recent findings are presented. Consistency is sought with the evidence noted in the earlier report. In essence, the recent time period is taken to be a separate or independent "experiment" to look for consistency with what was known previously.

ACKNOWLEDGEMENTS: Staff of the Occupational Disease Panel and Ms. Irene Rule obtained the references. Ms. Marlene Vaz helped in the preparation of the tables. Dr. Ron House, St. Michael's Hospital, University of Toronto, kindly provided an independent rating of the methodology of certain articles.

1.0 INTRODUCTION

Welding is an important activity worthy of being reviewed, in part because from 0.2 to 2.0% of the working population in industrialized countries has been reported to be engaged in welding (Stern, 1981). In the 1980s, it was estimated that up to 36,000 residents were employed as welders in Ontario (Hatch Associates, 1985). In the United States, it was estimated that more than 185,000 workers were employed as welders, brazers or thermal cutters in the US, and up to 700,000 workers carried out some welding during their work (NIOSH, 1988).

Although there are a large number of processes, a small group of these make up a large part of welding activity: the five processes, shielded metal arc welding, SMAW (also known as manual metal arc welding, MMA) and gas metal arc welding, GMAW (or metal inert gas, MIG) on mild steel (MS) and stainless steel (SS), and gas tungsten arc welding, GTAW, on aluminum make up 60-70% of all welding activity (Australian National Occupational Health and Safety Commission, 1990). Similarly, Stern (1983a) noted that SMAW using stick electrodes, and GMAW (using continuous wire) applied to MS, SS, and aluminum account for combinations practised by 70% of welders.

The welding environment is very complex, with the presence of numerous gaseous and particulate components (Figure 1). These constituents of welding fumes and gases can be classified into those intrinsic, and those outside or extraneous to the process (e.g. bystander exposure to asbestos) (Liss, 1985; IARC, 1990). Details of the processes, and brief reviews of the individual health effects of some of these specific contaminants (constituents of welding fume and gases) were included in the earlier review (Liss, 1985). No attempt is made to review these individual constituents here.

The consumable is the major source of fume. Fume, which makes up most of the particulate component generated during welding, is generated by volatilization of melted substances with subsequent condensation of solid particles from the gaseous state. Examples of the range of likely exposures in different processes were summarized in Liss (1985), and more recently by IARC (1990) and van der Wal (1988); the reader is referred to those sources. Morgan (1989) also commented on the multiplicity of processes, as well as how emissions and types of fume vary. In general as a result of the multiplicity of exposures, one cannot attribute health effects to specific components of the fume or to individual welding processes.

Examples of processes and process-dependent exposures:

Exposures to various other compounds can occasionally occur with the use of specific consumables or from surface coatings extraneous to the welding process.

Approach taken: For the most part the focus is on reports in humans; reports in animals are included where it adds or human data are lacking. We review acute effects first and then chronic effects. For the discussion of respiratory diseases, it should be emphasized that there is a high likelihood of welding fume reaching the alveoli (Morgan, 1989) due to its respirable size range.

2.0 METHODS

The following sources were used to identify as many relevant studies and reviews as possible:

1. In March 1995, a literature search of the Medline and NIOSHTIC data bases was conducted for this writer by the ODP, with medical subject headings "welding" and "health effects". All abstracts were reviewed and those papers which appeared relevant were retrieved, if not already in personal files.
2. Personal files
3. Recent review articles including Morgan (1989), IARC (1990), and Sferlazza and Beckett (1991).
4. References from these articles were obtained if considered relevant.

Rating Quality of Studies

The quality of the cohort studies of lung cancer and the morbidity studies of chronic non-malignant respiratory disease (symptoms, lung function) was rated independently by this writer and a second reviewer. For the studies of chronic respiratory disease (which were predominantly cross-sectional in design), we used a rating scheme (shown in Appendix 2) adapted from one previously used in reviewing carpal tunnel syndrome (Stock, 1991) and Dupuytren's Contracture (Liss, 1993). Similarly, for the cohort studies of lung cancer and welding published since 1985, a rating instrument was developed (Appendix 3) adapted from the Ontario Advisory Council (1983). Differences in rating were resolved by consensus.

3.0 ACUTE EFFECTS

3.1 Acute Bronchitis, Pneumonitis and Intoxications

1985 Review: Prior to 1985, numerous cases of fatal and non-fatal pneumonitis in welders had been described, associated with exposure to ozone, oxides of nitrogen, cadmium, lead, polytetrafluoroethylene, and phosgene (due to decomposition products generated from chlorinated hydrocarbons). Many of these incidents were due to welding in confined spaces, or welding and cutting on metal with unknown coatings or paints.

Recent findings: Unfortunately, case reports continued to be reported since 1985. The reports included acute pulmonary reactions associated with welding-induced decomposition of trichloroethylene (Sjogren et al, 1991); welding copper pipe using silver brazing solder containing cadmium (Inoue et al, 1994); a plate welder working with oxyacetylene torch on cadmium alloy (Yates and Goldman, 1990); and fever and symptoms after welding on steel painted with a polymer lacquer (Sjogren et al, 1991a). In this latter report, the paints contained epoxydized vegetable oils hardened by hexachloro-endomethylenetetrahydrophthalic acid anhydride (HETacid anhydride). Some of the decomposition products are chlorinated, and possibly hexachlorocyclopentadiene may be generated from HETacid. This highlights once more the need for welders to be aware of the materials used to clean or coat the base metal as well as the composition of consumable and base metal themselves.

Other acute intoxications: Lead can be considered to have both acute and chronic effects. Reports of acute lead intoxication continued to be published (Holness and Nethercott, 1988; Marino et al, 1989). In addition, lead exposure associated with cutting lead-painted plates with oxyacetylene torches during the refitting of ships was described by Landrigan and Straub (1985).

3.2 Pneumonia

1985 Review: There were reports of increased deaths from pneumonia among welders, that were not observed in their wives or compared to a referent group. Increased morbidity from pneumonia among welders, however, was not observed in two studies where it was examined.

Recent findings: In previous analyses of occupational mortality from England and Wales, the Registrar General found that welders had an excess of pneumonia (see Liss, 1985) with standardized mortality ratios (SMRs) of 184 (95% Confidence Interval [CI] 150-224) in 1959-63, and 157 (95% CI 121-200) in 1970-72. Coggon et al (1994) extended these findings by analyzing data for 1979-80 and 1982-90; they found that the mortality risk from pneumonia was attributable mainly to an excess of pneumococcal and unspecified lobar pneumonia (proportional mortality ratio 255, 95% CI 192-332). No excess was seen in men above age 65.

Because increases were also seen among men in other jobs that entail exposure to metal fume or heated metal (e.g. moulders and coremakers), the authors suggested that metal fume might be the cause. Alternately, the gases such as oxides of nitrogen and ozone, which increase susceptibility to bacterial infections in animals could be involved (e.g. Copestake, 1987). Newhouse et al (1985) found increased deaths from pneumonia among welders at a shipyard in England (10 vs 5.4 expected), as did Beaumont and Weiss (1980) (SMR 1.67; observed 19). In a cross-sectional morbidity survey of British shipyard employees, a history of pneumonia was not associated with exposure to welding fume but a history of pleurisy was (Cotes et al, 1989). Coggon et al (1994) concluded that "there are strong grounds for the classification of lobar pneumonia as an occupational disease in welders". Although the consistent findings over time are certainly striking, one peer reviewer suggested that what is needed "to test this hypothesis further, is a well-designed case-control study nested in an industrial population in which pneumonia mortality can be easily ascertained".

3.3 Metal Fume Fever

As summarized in my 1985 document, metal fume fever (MFF) (also known as brass founders' ague or Monday morning fever), is a relatively common, acute febrile illness of short duration that may occur during and after welding operations. The condition is thought to be caused by freshly formed fume. The symptoms, which may simulate a flu-like illness, come on 4 to 8 hours after exposure, and include thirst, dry cough and throat, metallic taste in the mouth, chills, dyspnea, malaise, muscle aches, headaches, nausea, and fever and chills. The symptoms and signs resolve by the next morning. It is associated with many types of fume, most commonly zinc, copper and magnesium.

The mechanism is not known. In my 1985 report, I noted "specific features of MFF, namely, that it can be reproduced in experimental animals, that it can be experienced on the first day by a new employee (no latent period) and that large proportions of the welding workforce (about 30%) are affected, are not consistent with features suggestive of an allergic basis for disease. ...while MFF has manifestations resembling an immunologic disorder... Conceivably, the mediators leading to the manifestations of chills, fever and leukocytosis, could be released by a direct (toxic) pharmacologic interaction of human cells with some component in the welding fume and not necessarily by an allergic reaction. It is possible that the more recently recognized elements of the immune system, such as interleukins are involved, but evidence is lacking at this time" (Liss, 1985).

Recent findings: In fact, a recent investigation by Blanc et al (1993) suggested that various cytokines released from pulmonary cells, tumour necrosis factor, interleukin-6 (IL-6), and interleukin-8 (IL-8), may be involved in the pathogenesis of MFF.

German investigators (Vogelmeier et al, 1987) examined exposure during welding by a locksmith who had had MFF symptoms. During challenge, the blood zinc level was elevated but the cadmium level was not; the temperature and peripheral blood leukocyte count rose. The total cell count in bronchoalveolar lavage fluid was 10 times normal, while the differential count indicated a marked increased in polymorphonuclear leukocytes (PMNs). Pulmonary function tests showed a slight decline in airway resistance but a significant decrease in inspiratory vital capacity, transfer factor, and arterial oxygen partial pressure. The authors concluded that MFF induces a high-grade alveolitis. No pulmonary fibrosis has been observed following MFF but the authors considered that the question remains open regarding whether the marked increase in PMNs is really harmless to pulmonary tissue.

Noel and Ruthman (1988) demonstrated elevated serum zinc levels in two cases of MFF, while Langley (1991) described a welder who developed MFF and reactive airways dysfunction syndrome (RADS) after welding.

Recent animal report: Lam et al (1988) reported that although previous work had shown 1-3 hr exposures to zinc oxide (ZnO) at or below 5 mg/m³ had only minor transient changes on lung function parameters, guinea pigs exposed for 3 hr per day for 5 days to 7 mg/m³ of freshly generated respirable ZnO particles demonstrated decreases in flow resistance, lung compliance, and total lung capacity (which recovered in 48-72 hr). Vital capacity and functional residual capacity and DL_co were also depressed. This suggested that the recommended TLV for ZnO of 5 mg/m³ may be inadequate to protect workers.

3.4 Acute (Short-Term) Changes in Pulmonary Function

1985 Review: The main previous study of this subject (McMillan and Heath, 1979) found no significant differences between lung function changes over the day between welders and controls; of note, the observers appeared to be blinded to exposure status in that study.

Recent findings: Four new studies addressed this issue. Akbar-Khanzadeh (1993) obtained pulmonary function tests (FEV₁, FVC, and transfer factor for lung for carbon monoxide (TL)) before and after the shift in 209 welders and 109 nonwelder controls in England. The controls were selected from office workers, jointers, fitters, drivers, staging makers and electricians. It was not stated whether the observers were blinded to exposure status. The two groups had identical age, height and proportion of cigarette smokers and daily number of cigarettes. The welders did not wear respiratory protection. In 24.5% of welding samples, the concentration of welding fume exceeded 5 mg/m³ , and in 6.7% of samples the concentration of iron oxide exceeded 5 mg/m³.

There were significant decreases from morning to afternoon in the mean change in all three pulmonary function indices among both welders and controls but the reduction was approximately four times greater among welders. There were no statistically significant correlations between the diurnal variations in lung function and daily tobacco, fumes or gases sampled except for acute reduction of FEV₁ which was positively correlated with levels of iron oxide produced while welding (p<0.05). Welders who did not use any ventilation system showed maximum reductions in TL value while those who used combined ventilation systems had increased TL values in the afternoon. The overall difference in mean diurnal variations in TL between groups working under different conditions was significant (p<0.01). Those with reduced pulmonary function did not differ from those without reductions in terms of age, height, baseline lung function or smoking habits.

Marquat et al (1989) reported contradictory findings. They studied lung function measurements before and after the shift for 5 consecutive shifts among 11 welders of zinc-coated steel, 10 nonwelders who were indirectly exposed, and 17 controls. Exposures were lower than in the study by Akbar-Khanzadeh (1993) with geometric mean concentrations in the three groups of 0.91, 0.44 and 0.40 mg/m³ for dust, and 34.0, 19.1, and 4.1 g/m³ for zinc, respectively. No statement regarding blinding of observers was given. On average, lung function parameters were higher at the end of the work shift in keeping with normal diurnal variation. Differences in mean changes between exposure groups were small compared to the intragroup variation; there were no significant differences (p>0.1) between the three groups in mean changes in lung function over the week. There was no consistent direction or value of correlation coefficient between changes in lung function over a work shift and concentration of dust and zinc measured during the shift. Of 14 comparisons (7 lung function tests and 2 exposures measures), only the change in peak expiratory flow was significantly correlated with dust (r=-0.18, p<0.05).

As part of a larger study, Kilburn et al (1990) examined pulmonary function across a Monday workshift in 31 subjects (7 welded SS, 14 black steel, and 10 did not weld but were fitters and helpers). No indication of blinding to exposure group was stated. No exposure data were given but among the men who welded SS, levels of serum chromium (Cr) increased 66% and urinary Cr increased 22% over the shift. Pulmonary function changes were less than 2%, did not differ between groups, and were not statistically significant. However, the group sizes were limited.

Most recently, Donoghue et al (1994) examined 20 welders and 20 nonwelders (representing 95% of those invited to participate). All had essentially never smoked and had similar baseline age, height and spirometry. They were studied on Monday, with no welding since noon on the previous Saturday; there was no indication regarding whether the observers were blinded to exposure status. The peak expiratory flow (PEF) was measured before the start of work and 15 minutes, 30 minutes and 1, 2, 4, 7, and 12 hours after the start of welding. The mean change in PEF among welders at 15 minutes (a decline of 1.67%) was significantly different from that among nonwelders (an increase of 0.79%; p=0.028), and the mean for maximum decline recorded among the welders (-4.85%) was significantly greater than that in the nonwelders (-2.14%; p=0.011). None of the welders had PEF declines of 20% considered diagnostic of asthma. However, 10 (50%) of the 20 welders compared to only 1 (5%) of the 20 nonwelders experienced a 5% decline in PEF (p<0.005). The authors considered the results suggestive of an immediate type reaction in welders similar to that seen in occupational asthma (OA). Unfortunately, exposure was not measured. There was no local exhaust ventilation and low use of respiratory protection.

Summary: Two of the four recent reports did not find significant acute changes in lung function over the shift, in agreement with the early report of McMillan and Heath (1979); however one should note that these were small studies with low power and therefore inconclusive. One of the two studies that did find such changes (Akbar-Khanzadeh, 1993) documented what appeared to be the highest exposures, and effects were seen among those not using any ventilation system. This is consistent with the occurrence of acute pulmonary effects during welding, but that the effects may be dose- (or indirectly ventilation-) related. This would not be surprising given the known irritant effects of gases such as ozone and NO₂, as well as other constituents of welding fume.

3.5 Asthma

Vandenplas et al (1995) recently described a welder who developed asthma after 3 months of GMA welding on MS. He demonstrated both late and dual reactions after occupational-type challenge with welding on uncoated MS, suggesting a hypersensitivity rather than an irritant mechanism. Recently, Hendrick et al (1996) demonstrated (in abstract form), an increase in methacholine airway reactivity among shipyard welders and caulker burners in the U.K, compared with male school leaver controls, associated with exposure to welding fume, presumably through a nonspecific "irritant" mechanism.

Wang et al (1994) conducted a follow-up study of the welding work force at four factories in Sweden. They used company records to locate those who had been employed after January 1980, and who had at any time in the previous 10 years worked as welders; they also attempted to locate those who had left the company. The subjects were interviewed by questionnaire and the investigators established two cohorts based on data from the questionnaire: SS welders, defined as those who had been welding less than 10 years before the start of the study and who had welded for at least 6 months (welding time in SS > 50% of total time welding, exceeded 4 day/week and 4 hr/day for at least 6 months), and MS welders, selected with similar criteria. Both cohorts were studied for evidence of asthma, including ex-welders and active welders. There were 209 active welders (67 SS, 142 MS), and of 227 who had left welding, 209 (92%) of the ex-welders were located, and 187 responded (57 former SS, 130 former MS). A reference group of vehicle assembly workers who had never welded was also asked to complete the questionnaire. Bronchial responsiveness was determined among active welders by methacholine challenge. Subjects were considered to have asthma if they had two or more symptoms of excessive cough, wheeze, chest tightness or episodic dyspnea and the methacholine test showed bronchial hyper-responsiveness. Subjects with symptoms of asthma who did not perform this test were denoted as possible asthma. There was no difference in the incidence of welding-associated asthma (5% for SS, 7% for MS; 5 and 7 per 1000 welding-years, respectively). Bronchial responsiveness and lung function in active welders was normal, and did not differ between MS and SS welders. These estimated incidence rates of asthma can be compared with estimates of 2.1 per 1000 per year in a U.S. population (McWhorter et al, 1989), and rates of physician-diagnosed asthma of 4 per 1000 per year (Lebowitz, 1989).

Summary: In a review article, Sferlazza and Beckett (1991) commented that given the prevalence of asthma and the large number of regular welders, this suggests an infrequent occurrence of OA associated with welding. On the other hand, Meredith et al (1991) found OA was reported more commonly among welders than in the average working population. The recent prospective study by Wang et al (1994) provides little evidence of an increased incidence of asthma among welders compared to the general population, and gave no support for an increase, if any, being due to nickel and chromium in SS welding as suggested by the cases reported previously by Keskinen et al (1980).

4.0 CHRONIC RESPIRATORY DISEASES

4.1 In Vitro Cytotoxicity and Fibrogenicity of Welding Fume

1985 Review: Several studies, for example those by White and colleagues (1983) and Stern and Pigott (1983) showed that welding fumes from SS welding processes were particularly toxic. Cytotoxicity was noted to increase in the following order: fumes from MS rutile electrodes < MS basic < SS. Cr(VI) particles were toxic to macrophages; the toxicity of SS fume was attributed to Cr(VI) content, and MMA/SS fume was more toxic than GMA/SS fume.

Recent findings: Pasanen et al (1986) also examined the cytotoxic effects of fume on rat alveolar macrophages (AMs), and examined cell viability with trypan-blue dye exclusion. They found MMA/SS and MMA/MS to be cytotoxic, while MIG fumes of SS and MS had markedly smaller effects. Only the effects of MMA/SS were diminished when water-soluble components were extracted from the particles. Diluted solutions of potassium chromate similarly showed that hexavalent chromium may be responsible for the cytotoxicity of MMA/SS. They considered that the low cytotoxicity of MIG welding fumes was related to their chemical composition, which differed from MMA/SS (as the former contains mostly poorly water-soluble components).

Hooftman et al (1988) investigated whether toxicity was restricted to SS welding fume and estimated the contribution of chromium to the effects observed. They examined fume from MMA/SS, MIG/SS, MMA/CI (cast iron), MMA/MS, and MIG/MS using test criteria of viability (using trypan blue exclusion), phagocytic capacity, and morphology of the macrophages on bovine AMs. Consistent with the earlier reports, they found, for cytotoxicity, that the toxicity of the fume increased in the order: MIG/MS, MMA/MS, MMA/CI and MIG/SS, MMA/SS. They considered that MS fume (and MIG/MS particles in particular) are hardly toxic at all, having the same effects as glass beads. Soluble Cr(VI) appeared to be far more toxic than Cr(III). In terms of soluble chromium content, the results for the welding fume particles were comparable with those from chromium from K₂CrO_4. In other words, it seemed that the toxicity of most welding fume particles paralleled their content of soluble chromium. Fume from MIG/SS and MMA/CI were more toxic than one would expect based on this parallel, suggesting other factors play a part.

Stern et al (1988) also examined the in vitro cytotoxicity of welding fume and found somewhat similar results. They concluded that MMA/SS fumes are toxic (and genotoxic) apparently because of their soluble Cr(VI) content, and MIG/SS fumes are toxic at sufficiently high doses. The toxicities of MIG/Ni and MAG/SS which have insoluble fractions are within a factor of 2 of MS fumes; none of these fumes contain appreciable concentrations of Cr(VI).

Li and Yun (1988) compared the effects on collagen silica (95% quartz) and welding fume dust following intratracheal installation into lungs of rats. They examined collagen using ELISA staining and histological findings. Silica produced marked (significant) increased in both Types I and III collagen (about 8-9 fold) and increased the ratio of I/III from about 1.4 to 2. Welding fume produced a much smaller increase (less than doubling) and the I/III ratio stayed at about 1.4. They concluded that welding fume induced a slower and milder lung fibrosis compared to silica.

Finally, Ben Otmane et al (1992) examined ultrastructural changes on electron microscopy in guinea pig AMs and enzyme leaking (ß-glucuronidase activity) in guinea pig AM homogenate following cell culture with welding fume. They found that MMA/SS welding fume had relatively high cytotoxicity confirmed by an increase in culture medium -glucuronidase activity which they felt might be due to a soluble Cr(VI) compound. MIG/Ni and MIG/SS showed similar ultrastructural changes but the cellular damage was much more prominent for MMA/SS.

Summary: Welding of stainless steel generates the most toxic fumes, and MMA/SS particles were far more toxic than MIG/SS particles. The observed cytotoxic effects are largely due to the soluble chromium content of the fume particles, particularly those from MMA/SS welding. Insoluble compounds may play a part. The authors concluded that since the fibrogenic power of particles is known to be related to their cytotoxicity to AMs, particles from MMA/SS welding should be regarded as potentially fibrogenic. This was a similar conclusion to that reached earlier by Stern and Pigott (1983). Since phagocytosis is affected, this could make the lungs more vulnerable to inhaled particles, including microorganisms (perhaps this could explain the findings of increased pneumonia).

4.2 Chronic Respiratory Morbidity

1985 Report: Although not all studies were of very good quality, the investigations available at that time were consistent in suggesting an increased prevalence of one or more chronic respiratory symptoms (dyspnea, cough, sputum, wheezing, chronic bronchitis) in welders compared to referents. Of 13 studies, 9 revealed such evidence for one or more symptoms that was "statistically significant" and in 7 of these, seven reported data separately for non-smokers, and 4 showed significant excesses in non-smokers for one or more symptoms, with prevalence rate ratios of 2 to 4. Few studies examined the evidence for an effect due to duration of welding, and most did not use multivariate analyses. For pulmonary function, keeping the limitations of cross-sectional studies in mind, the differences in lung function seemed fairly consistent, with decreases in FEV₁ and measures of small airway function (MEFR, FEF₅₀, FEF₇₅), in a number of studies. Fewer studies documented such decreases in non-smokers. The evidence was limited for an association with duration of exposure. Kilburn (1986) suggested an interaction between smoking and welding fume but this needed to be confirmed.

Recent findings:

The results are presented separately for (I) symptoms (focusing mostly on chronic bronchitis, as a possible marker of chronic lung disease), and (ii) pulmonary function.

Assessment of validity of studies: All of the studies identified from the literature search were assessed independently by two raters using a validity assessment questionnaire (Appendix 2), adapted from Stock (1991). It included the seven criteria considered by Stock (1991): absence of selection bias, absence of nonrespondent bias, comparability of study and control groups, accounting for confounders, validity of exposure measures, validity of outcome measures, and blinding of assessors. Particular note was made as to whether the findings were reported separately for non-smokers. The interobserver agreement of the ranking was calculated using the kappa statistic (Sackett et al, 1985). Differences were resolved by consensus. A separate criterion, for study design, was added subsequently (scored 1 for cross-sectional only, 3 if a longitudinal component was included).

Studies Identified

Fourteen studies were identified; Table 1 shows the main features of these studies. Two studies (Kilburn et al, 1989; Hjortsberg et al, 1992) did not report symptoms. Three studies had longitudinal components: Mur et al (1989) a follow-up of the 1985 study, Chinn et al (1990), and Chinn et al (1995). The findings of the validity assessment of the methodology of the studies are shown in Table 2. Table 3 presents the study results for chronic bronchitis, and Table 4 the study results for pulmonary function.

Validity Assessment (Table 2): The kappa for interobserver rating was 0.40, indicating fair to moderate agreement. The quality (ranking) did not vary widely among the studies, ranging from 13 to 17 out of 21, with median rank about 14. The greatest weakness was the lack of blinding of examiners. All studies except one (Chinn, 1990) had scores of 2 or more on the three criteria of comparability of groups, valid exposure measures, and valid outcome measures considered by one investigator (Stock, 1991) as the major threats to validity in such studies, and so none were excluded from further assessment. However two studies (Kilburn et al, 1990; Nielsen et al, 1993) did not present the findings stratified by smoking status.

Study Findings

4.2.1 Symptoms (Chronic Bronchitis; Table 3)

Studies without stratification for smoking status: Two studies (Kilburn et al, 1990; Nielsen et al, 1993) did not present their findings stratified by smoking status. In these studies, the prevalence of chronic bronchitis among welders was 3 to 4 times that in the controls in these studies. A third report (Marquat et al, 1989) stated there was no difference in symptoms but no data were provided.

Nonsmokers:

Of the other 8 studies, one found a slightly (but not significantly) lower prevalence of chronic bronchitis among welders (Mur et al, 1985) (Table 3). Two studies found little or no difference (Sjogren et al, 1985; Mur et al, 1989), and in a third, Chinn et al (1995), in their cross-sectional analysis using multivariate techniques, found that among smokers and non-smokers combined, trade as a welder or caulker/burner was not a significant predictor for chronic bronchitis but that smoking and trade interacted significantly, with increased symptoms among smokers.

On the other hand, the prevalence of chronic bronchitis was reported to be higher among welders in the other four studies: two-fold higher by Zober (1985), 16% vs 0% (p<0.05; OR not calculable) by Lyngenbo, three-fold higher (including ex-smokers) by Cotes (1989), and four to five-fold higher by Groth (1989; p<0.01). Groth demonstrated evidence of a dose-response relationship with level of welding exposure (Table 3).

Other symptoms: At the initial assessment, Chinn et al (1995) found that trade as welder or caulker/burner (W/CB) among nonsmokers was related to the prevalence of wheeze, current cough, cough > 3 months, and a history of producing phlegm for > 3 months. Cotes (1989) found wheeze significantly increased among non-smokers (OR 2.7).

Smokers:

Of the 8 studies available, the prevalence of chronic bronchitis was less frequent (but not significantly so) among welders in the follow-up study by Mur (1989) and among heavier smokers in the initial report by Mur (1985). There was no difference found in chronic bronchitis prevalence among smoking welders and controls by Zober (1985) and Chinn (1995, at cross-sectional analysis), found that trade was "not significant" in the logistic regression for cough and phlegm for > 3 months among smokers and non-smokers combined.

On the other hand, the prevalence of chronic bronchitis was increased but not significantly, by Sjogren (1985; OR 1.7) and among light smokers by Mur (1985; OR 1.9). The prevalence among smoking welders was significantly increased in three studies: Cotes (OR 2.3), and Groth (about 2-fold in each smoking group). Among smokers alone, Chinn (1995) found that the prevalence of cough and phlegm for > 3 months was related to trade (OR 2.8). There was some evidence of dose-response given by Groth (1989) in each of the smoking groups.

Other symptoms: Chinn et al (1995) found trade to be a significant predictor among smokers alone for cough > 3 months (OR 3.5), phlegm > 3 months (OR 2.2), and wheeze (1.8), and among smokers and nonsmokers combined for phlegm (OR 2.9), and wheeze (OR 2.3), while controlling for smoking.

Longitudinal analyses: Mur (1989) found that the evolution over 5 years of respiratory symptoms (chronic bronchitis, breathlessness, and asthma) was not significantly different between welders and controls. Chinn (1990) found that during follow-up, an increase in the grade of breathlessness (OR 2.8) but not chronic bronchitis or wheeze to be significantly related to trade as a welder but this analysis was limited to those subjects seen at follow-up, only a small proportion of whom were still active. These analyses were adjusted for smoking, but smoking status-specific results were not presented. After controlling for smoking, Chinn (1995) found that trade as a W/CB was significantly associated with the development of chronic phlegm during follow-up (OR 2.8) but was not a significant predictor of the development of chronic cough, chronic bronchitis or wheeze.

Evidence for interaction: Cotes et al (1989) suggested that there was evidence for an interaction between smoking and exposure to fumes as a W/CB in causing chronic bronchitis and other symptoms. Chinn et al (1995) (cross-sectional analysis) found a significant interaction between smoking and trade for cough and for chronic bronchitis.

4.2.2 Pulmonary function (Table 4)

4.2.2.1 Large airways

No differences were found in six studies: Sjogren (1985; in FEV₁ and FVC); Mur (1985; and in 1989 follow-up), Kilburn (1989), Hjortsberg (1992) (only non-smoking welders studied), and Nielsen (1993) (not stratified for smoking). In a seventh study, Marquat (1989) found that the regression coefficients for welders vs controls for tests of large airways were negative but not significant.

Kilburn (1990) found only small non-significant decreases among nonsmokers but significant declines among smokers of about 5%. Lyngengbo (1988) studied nonsmokers only and found significant declines in FVC and FEV₁. In the cross-sectional analysis (initial assessment), Chinn (1995) found that trade as a W/CB was associated with an increase in expiratory reserve volume, and functional residual capacity. At follow-up, analyzed cross-sectionally, these investigators found that the lung function of referents (other trades) was superior to those of welders and caulker/burners who remained. However, at the initial assessment for the same workers, the lung function (e.g. FEV₁) of welders who were to remain (working) did not differ from other subjects, suggesting that the decline was associated with work but the role of selection bias is not clear, given the small proportion followed up.

Duration of exposure or exposure index: Marquat (1989) found that the regression coefficient for years of welding, after adjusting for smoking and other factors, was negative and of borderline significance for FEV₁ and FEV₁/FVC. Cotes (1989) found that among ever smoking welders, the fume exposure index contributed to FEV₁ and FEV% (but not FVC).

Longitudinal analyses (Table 4): Mur (1989) did not find that the "evolution" of pulmonary function differed between groups. Chinn (1990) found that the annual decline in FEV₁ was related to trade as a welder, with that among a smoking welder about 3 times that of a non-smoking nonwelder. In welders but not others, atopic status contributed to the annual decline in lung function but not to the risk of developing respiratory symptoms. These investigators also found that for PEF and PEF, the annual decline was greater in men whose trade was a W/CB. Chinn et al (1995) presented data showing that trade as a W/CB, independently of whether or not a man had left the shipyard, was associated with adverse changes in some lung function tests including inspiratory vital capacity and residual volume. Smoking appeared to interact with shipyard trade to impair development of expiratory vital capacity. Continued shipyard work as a W/CB was associated with enhanced deterioration in FEV₁and in PEF (the latter confined to smokers - that is, there was a significant interaction). Chinn (1995) also found that the decline in FEV₁ was related to whether exhaust ventilation was used 100% of time.

Presence or Absence of Restrictive or Obstructive Patterns:

Restrictive Patterns (Table 4): Among nonsmokers, the prevalence of restriction was found to be increased by Zober, 5-fold (but not significant) (1985) and by Lyngenbo (1988) 8% vs 0% (also not significant). Among smokers, Zober (1985) found no significant difference in restrictive changes.

Obstructive Patterns: Among nonsmokers, obstruction was reported to be about 2 times more prevalent by Zober and Lyngengbo (both not significant). Among smokers, Zober found obstruction was less frequently present among smoking welders than smoking nonwelders at young ages (2% vs 14%), while at older ages, it was more frequent among welders (8% vs 0%, p<0.05).

4.2.2.2 Small airways

Results not stratified for smoking status: One study (Nielsen et al, 1993) did not present results stratified by smoking status. They found no difference in spirometry or in one small airway test (closing volume, CV), but another test, slope of the alveolar plateau (phase III) by single breath N₂ washout was increased significantly after methacholine (p=0.01) in welders compared to controls. In addition, long-term welders had significantly higher phase III readings than short-term welders and controls, thought mainly to apply to aluminum welders. Mur (1985) reported that MEF_50%, not stratified for smoking, was significantly lower for welders using manual vs semi-automatic processes (p<0.05).

Nonsmokers: No differences in small airways function were reported by Mur (1985) at the initial assessment but in the cross-sectional analysis of the follow-up study (Mur, 1989), there was evidence for decreased MEF_25%. Significant decreases were observed by Kilburn (1989) and Kilburn (1990) for FEF_75-85, and Lyngenbo for an increase in the slope of the alveolar plateau. Hjortsberg et al (1992) reported larger volume of trapped gas (VTG), of borderline significance, among welders compared to referents and significant increases in VTG after methacholine among welders but not among referents.

Smokers: Mur (1985) found no differences at the initial assessment (1985) or at follow-up (1989) analyzed cross-sectionally. Kilburn (1989) and (1990) found significant declines among welders in FEF_25-75 and FEF_75-85 of 7-15% and 9-25%, respectively.

Longitudinal analyses: Mur (1989) found the decline in MEF_25% over time was significant only among welders. Chinn (1990) found that for various spirometric indices (MEF_50%, MEF_50%) after allowing for age and smoking, the annual decline was greater in men whose trade had ever been W/CB compared with trades that did not involve these tasks. Chinn (1995) found that over follow-up, after adjusting for smoking, continued trade as a W/CB was associated with enhanced deterioration in FEF_75-85.

Diffusing capacity: Among nonsmokers, diffusing capacity was normal among welders in most studies when examined, although Lyngengbo (1988) found it to be decreased. In smokers, it was reported to be decreased by Mur (1985) and Mur (1989), but normal by Kilburn (1990). Chinn (1990) found that changes in diffusion over follow-up were not related to trade. At the cross-sectional analysis, Chinn (1995) reported that trade as a W/CB was associated with a decrease in transfer factor.

Evidence for interaction between welding and smoking: Mur (1985) found evidence of an interaction for lung transfer (greater in smokers) and found the effects of welding in nonsmokers and light smokers to be negligible. Kilburn (1989) suggested an interaction of welding with smoking in producing lung function decrements. Cotes (1989) also found that the effects of fume exposure were mainly confined to smokers and ex-smokers. Kilburn (1990) reported that nonsmokers showed smaller decreases in lung function than did smokers, consistent with a synergistic effect on airways of welding fume and tobacco. Chinn (1995) reported that smoking appeared to interact with shipyard trade to impair development of expiratory vital capacity, and that the decline in PEF (longitudinally) was limited to welders who smoked (significant T.Sm term). On other hand, as noted, Zober (1985) found the prevalence of restrictive lung function abnormalities was increased in nonsmoking but not smoking welders compared to their respective controls.

Summary:

Symptoms: There was improvement in study quality since 1985; some studies examined nonsmokers only. The data suggest an increase in the prevalence of chronic airways symptoms (including chronic bronchitis as a marker of severe disease as well as other symptoms), that was seen in some but not all studies. In the 11 cross-sectional studies, increases were seen in 2 studies not stratified for smoking (3-4 fold higher prevalence), and in both nonsmokers (4 of 8 studies) and smokers (significant increase in 3 of 8 studies and non-significant increase in 2 others). This is consistent with the earlier review (Liss, 1985). There was evidence of an interaction in some studies with the effect greater among smokers. The strength of the association is moderate (about 2-fold, in those studies demonstrating an effect), but effects were not seen consistently. Evidence for a dose-response relationship was provided in only one study, with increasing "degree of welding exposure" (a measure which included duration of welding) (Groth, 1989), and this held across smoking strata.

The publication since 1985 of studies with longitudinal design (as was recommended) also represents an improvement over the quality of studies available a decade ago, as one hoped this would clarify some of the limitations of cross-sectional studies. In these longitudinal studies, some symptoms such as phlegm and increase in breathlessness (but not chronic bronchitis or wheeze) were related to trade. However, as noted, these studies were limited by the small proportion available for examination or who were currently active at follow-up. For example, Chinn (1990) studied 488 (88%) of 609, but 425 of these had retired or been made redundant, and Chinn (1995) restudied only 346 (55%) of 625; hence, selection bias was possible.

Pulmonary function: As was found previously (Liss, 1985), the assessment of pulmonary function is limited in that most studies were cross-sectional in design. Impairment in large airways was observed in only a small minority of studies, and only two studies provided evidence supporting an association of pulmonary function with duration or index of exposure. Small airway function was affected somewhat more frequently than large airways (up to 7 studies in smokers, nonsmokers or both); nonsmokers were also affected but again, there was some evidence for an interaction with smoking. Zober (1985) found a higher prevalence of obstructive abnormalities in older smoking welders.

As with symptoms, longitudinal studies have now been conducted, and tend to show changes of enhanced deterioration in both large airways (in two studies) and small airways (in all three). However, caution is required in interpreting the data, in part because the participant drop-out rate has been too high to make definitive statements. The clinical importance of the pulmonary function changes reviewed above remains to be determined.

Are these findings causal?

Magnitude of effects: Chinn (1990) found that the proportion of variance explained by trade was on average half that due to smoking except when atopy was included in the analysis. For welders who smoked, the decline in FEV₁ was three times that of non-smoking nonwelders. Chinn (1995) found that the effects on pulmonary function were independent of and at least as large as those due to smoking. As noted, Kilburn (1989; 1990) found declines in small airways of 6-17% in nonsmokers and 15-25% in smokers. Cotes (1989) considered that the effect of fume, on average, was similar to that of being a smoker.

Consistency and temporality: Adverse effects were not seen consistently, that is, in some but not all studies (generally fewer than half). Temporality is not really addressed in the cross-sectional studies but is taken into account in the longitudinal studies. Welders had increased development of respiratory symptoms (but not chronic bronchitis) in two of the three longitudinal studies, and some markers of excess deterioration in pulmonary function in all three.

Dose-response: Groth (1989) presented evidence of dose-response relationships across smoking strata for symptoms but there is scant evidence available for an association with dose or duration of exposure for pulmonary function. On the other hand, several other findings add to the consistency of the adverse effects of welding fume and gases on pulmonary function and constitute indirect evidence for an exposure-response relationship. First, Mur (1985) reported that small airway function (MEF_25%) was poorer among welders working in confined compared to open spaces. Second, this study also found small and large airways tests were poorer among those performing manual vs semi-automatic welding processes (Table 4). Third, Chinn (1995) found that the excess decline in FEV₁ was less among those who reported using exhaust ventilation 100% of the time. An association between welding exposure and chronic obstructive pulmonary disease makes biologic sense, given that a number of fume and gas components are respiratory irritants. Occupational exposure to fumes or gases estimated by job exposure matrices was related to a decrease in FEV₁ in some analyses in the French Cooperative PAARC (Pollution Atmosphérique et Affections Respiratoires Chroniques) survey (Le Moual et al, 1995). Thus, only some of the criteria for causality are met.

Overall, the studies are of better quality than a decade ago, and the findings are somewhat more convincing for an association with non-malignant respiratory effects. However, many of the studies involved shipyard welders, and the applicability to Ontario welders is uncertain.

Consistent in general with these findings, Wanders et al (1992) recently examined "medical wastage" among 548 Dutch shipyard welders and 1409 controls (shipwrights and engine fitters) employed at the same shipyard as part of a 40-year cohort study. They contributed 5227 and 17,005 person-years of observation, respectively. Total medical wastage was defined as leaving for medical reasons including under the Work Disability Act, invalidity pension, death, selected employment and voluntary discharge for medical reasons. The only diagnostic category of medical wastage that was significantly different between the two groups was for non-malignant respiratory disease (greater among welders), with an incidence density ratio of 4.2 (90% CI 2.4-7.4), adjusted for age, calendar period and duration of employment as welder or control. The authors concluded that it underscores the "need to reduce the large excess of respiratory diseases among shipyard welders". A contrary view was recently provided by Morgan (1995) who concluded that McMillan and colleagues "studied all aspects of lung function and diffusing capacity and shown that welding and welder's siderosis was not associated with significant respiratory impairment, with the possible exception of a greater prevalence of airways obstruction among smoking welders".

Final note: For completeness, one could note criticisms of the reports by Kilburn (1989, 1990), raised recently by Jones et al (1995). The reference group used by Kilburn had been studied in the early 1980s, and involved a different group of subjects (from Michigan), collected by different investigators (Miller et al, 1986) for a different purpose. The study group was volunteer, which may have resulted in bias towards a worse health status, while the reference group was a random sample of a geographically defined population. The reference group was also screened to exclude those with common respiratory symptoms or diagnoses, angina or diagnosis of coronary artery disease. In response, Kilburn et al (1995) replied that "much rhetoric has been expended by other critics as well as Jones" with respect to selection bias, and emphasized that both groups were volunteers.

4.3 Siderosis and Fibrosis

1985 Report: Siderosis, due to prolonged pulmonary deposition of iron (oxide) particles appearing as nodular radiodensities on chest x-rays, is the most commonly occurring form of pneumoconiosis in welders (Palmer, 1983). Siderosis is usually classified among the benign pneumoconiosis (Parkes, 1982) as iron oxide is considered to be inert. Attfield and Ross (1978) reported the most detailed study of the relationship between the prevalence of small round opacities of class 0/1 or higher (larger than 1 mm "siderosis") and welding exposure based on chest x-rays from 661 British shipyard welders (see Liss, 1985). No cases of small round opacities 0/1 or greater appeared before 15 years exposure and the prevalence then increased with age or with length of exposure reaching over 30% among those with greater than 45 years' exposure.

Siderosis has generally been assumed to be benign and unassociated with respiratory symptoms (Morgan and Seaton, 1984) based on the absence of fibrosis both in animals administered iron oxide and in lungs of welders, and on the absence of pulmonary function abnormalities in welders with marked radiographic abnormalities (Morgan and Kerr, 1963). On the other hand, there are case reports of welders with dyspnea and respiratory symptoms, impairment of lung function, x-ray opacities and extensive fibrosis when biopsied (Liss, 1985). However, some of the cases worked in environments with silica as well as iron (suggesting mixed dust fibrosis). Stern et al (1983) reviewed the fibrogenic potential of welding fume, including the 90 or so published case reports which referred to irreversible pulmonary fibrosis in welders supported by tissue pathology at biopsy or autopsy. They suggested the possible role of NO₂ in fibrosis. In 1985, I concluded that "as there was no estimate for the incidence of pulmonary fibrosis in welders (or for that matter, in the general population), it is not possible to demonstrate if, in fact, an excess of pulmonary fibrosis in welders exists". Moreover, if welders face a possible fibrogenic hazard (Stern and Pigott, 1983), it has not been possible to establish a (the) fibrogenic agent by epidemiological methods.

Recent findings: Morgan (1989) noted, as have previous writers, that welders' siderosis is characterized by the deposition of iron particles in the lung parenchyma. Most of the iron particles have been ingested by AMs while some are seen lying free in the alveoli. He noted, referring to his early report (Morgan and Kerr, 1963), that the alveolar septa are not thickened and there is no alveolitis. He commented on the occasional reports of fibrosing alveolitis or chronic interstitial fibrosis and one case in particular in which he felt the subject had idiopathic pulmonary fibrosis and that the little iron in the lungs was not ferric oxide but hemosiderin (Morgan, 1989). More recently, Morgan (1995) commented that there was "little doubt that in its pure form, siderosis does not lead to pulmonary impairment".

Despite this comment, the epidemiologic studies (see above) continue to suggest increased symptom prevalence and some abnormalities of pulmonary function among groups of welders. What evidence is provided by the recent original reports regarding fibrosis?

Case Reports: Lasfargues et al (1991) described a 56 year old nonsmoking welder (arc welder for 30 years) who was noted to have siderosis (discovered from radiological abnormalities) and who developed fibrosis in the absence of any associated silicosis. Lung biopsy revealed patchy interstitial fibrosis. A case of chronic beryllium pneumonitis was reported from Scotland associated with exposure due to "spot welding" in an electrical engineering firm (Monie and Roberts, 1991). Glass et al (1994) described a 32-year old welder from New Zealand who had welded since age 17 repairing farm machinery, and manufacturing animal feeders and cages, and then had not welded for 4 years. He smoked five cigarettes per day. In August 1989, after he began (MIG) welding again, on galvanized steel frames, he suffered two relatively brief intense exposures to welding fumes each under relatively confined space conditions, indoors with poor ventilation. Three months after starting work he developed shortness of breath, could no longer participate in recreational running, and by February 1991, was no longer able to continue welding. Investigations revealed restrictive lung disease with severe reduction in diffusing capacity without airway obstruction or bronchial hyperresponsiveness. The results were indicative of chronic interstitial lung disease (CILD). The authors noted that to date, CILD had not been reported in association with galvanized welding or other zinc oxide exposures. Figueroa et al (1992) described two cases of hard metal interstitial pulmonary disease (one fatal) in workers employed in the same area of a metal coating plant using the detonation gun process for applying a durable metal surface to metal parts. In this welding, a mixture of powdered metals, including tungsten carbide and cobalt, was heated by ignition of a flammable gas and propelled from the end of the "gun" at high temperature and velocity to form a welded metal coating.

Epidemiological investigations: Kennedy et al (1985) attempted to determine if mineral dust or fume exposure in smokers resulted in additional changes in small airways structure and function. They studied 25 subjects exposed to dust or fume for more than 10 years selected from an ongoing study of pulmonary structure and function based on patients admitted to hospital for surgical resection of a lobe or lung because of lung cancer (13 miners exposed to dusts and 12 others exposed to other mineral dust or fumes, including 5 welders), and 25 control subjects admitted to the same study who reported no occupational exposure to dust or fume of any kind, matched for lobe resected, age ±3 years and smoking history. Membranous and respiratory bronchioles were graded for emphysema and the presence and degree of mural inflammation, fibrosis, smooth muscle hypertrophy, pigment, squamous metaplasia and goblet cell hypertrophy. There was no statement regarding whether observers were blinded to exposure. There was significantly greater fibrosis in the walls of membranous bronchioles and increased goblet cell metaplasia in the epithelium of the airways of the exposed group (p<0.01). There were no significant differences between the groups with respect to the respiratory bronchioles. When the exposed group was divided according to occupation into miners and nonmining exposed group and each subgroup compared with the corresponding control group, the results revealed that the excess fibrosis and goblet cell metaplasia was significant in both groups. Separate results for the welders were not presented. There were no differences in pulmonary function between the groups. The authors concluded that this supported the concept of airway fibrosis as a nonspecific reaction to mineral dust and fume; and that occupational exposure to mineral dust and fume results in a chronic inflammatory response (structural changes) in peripheral airways that are greater than those seen with smoking alone but that the changes were not associated with greater abnormalities in lung function.

Funahashi et al (1988) conducted histological examinations on lung tissue obtained from 10 symptomatic welders, ages 31 to 63 (mean 49) with duration of welding 8 to 40 years (mean 23), who had symptoms of cough and dyspnea, and abnormal radiographs (diffuse nodular or reticulonodular patterns). Pulmonary function tests showed restrictive impairment in seven, mild to moderate airways obstruction in two, and reduced diffusing capacity in three of nine (who also had restrictive impairment). Nine had open lung biopsies for diagnosis and in one case the tissue was obtained at autopsy. The tissue specimens were processed for tissue elemental analysis by energy dispersive x-ray analysis (EDXA); silicon/sulphur [Si/S] and iron/sulphur [Fe/S] ratios were compared with 10 age-matched controls and 10 cases of silicosis. The following table shows the main pathological findings, as interpreted by two pathologists.

The pathologists agreed within one grade; differences were resolved to the lower grade. All subjects had some degree of fibrosis and this was moderate to pronounced in five; alveolar wall thickening was moderate to pronounced in five. The elemental content in tissue showed that the mean Si/S ratio was no different between controls and welders whereas patients with silicosis had a significantly higher ratio than controls and welders (p<0.005). The mean Fe/S ratio was slightly but not significantly higher in patients with silicosis than in controls, while the Fe/S ratio was significantly higher in welders than in controls and silicotics (p<0.0025). No other elements were found to be raised in welders. Interstitial fibrosis is a reaction of lung tissue to various insults. They noted that the fact that many iron containing particles were seen in the fibrosed alveolar septa suggested that the observed fibrosis is a reaction to those particles (although this did not constitute proof). They felt that it was important for clinicians to recognize that "welders who have no exposure to silica or asbestos may develop interstitial fibrosis leading to respiratory symptoms and physiological abnormalities although it is uncommon". They concluded that (1) interstitial pulmonary fibrosis is seen in some welders; (2) the association of welders' pneumoconiosis and interstitial fibrosis appears to be more than coincidental; and (3) the cause of the fibrosis did not appear to be coexisting silicosis, as silica concentrations in the lung were within normal limits.

Summary: These recent investigations show that interstitial fibrosis occurs in welders (in one study, among those with radiological changes); that, unlike early reports from the 1960s, this does not seem to depend on the presence of silicosis; and that there are small airway (possibly early emphysematous) changes. It is not clear if the changes are related to iron or other constituents of welding fume and gases; the possible role of cytotoxicity of welding fume, especially SS fume, has been discussed above. As was the case in 1985, there are still no estimates of the incidence of interstitial fibrosis among welders to compare to that in the general population. It is possible, as noted by Billings and Howard (1993), that radiological siderosis could be a marker of serious welding fume exposure.

5.0 NONRESPIRATORY CHRONIC EFFECTS

5.1 Neuropsychiatric symptoms

Sjogren et al (1990) assessed neuropsychiatric symptoms in 65 welders exposed to aluminum (Al) and 217 railroad track welders in Sweden using a previously validated questionnaire (Q16). The questionnaire was initially sent to 308 welders, with a 92% response rate. Logistic regression was employed to examined the relation between exposure, age and occurrence of neuropsychiatric symptoms. Welders exposed to aluminum, lead or manganese for long periods had significantly more neuropsychiatric symptoms than welders not exposed to these metals; the authors suggested that detailed psychometric studies should be performed. It should be emphasized that the outcome here was subjective, and may reflect metal exposure in general, not necessarily features of the welding environment in particular. Sjogren and Elinder (1992) subsequently noted that long term Al welders have been shown to have increased urinary Al, and suggested, based on this study by Sjogren et al (1990) and the known effects of Al seen with dialysis encephalopathy at very high Al concentrations, that a dose-response relationship existed between Al welding fume exposure and effects on the central nervous system.

More recently, Hänninen et al (1994) examined 17 male Al welders from a ship building company in Finland engaged in welding for 2 to 27 (mean 15) years but engaged in MIG welding on Al for only the last four years. The authors conducted a series of neuropsychological tests, and assessed subjective symptoms and moods (symptom questionnaire and Profile of Mood States, POMS), serum and urine Al, and quantitative EEG (QEEG). The mean scores for the tests for psychomotor, visual and spatial abilities in the group fell within the "good-average range" and the means of memory tests and tests for verbal ability were within the average range of unpublished standardization data of the Finnish Institute of Occupational Health. However, there was a negative association between all four memory tests and urinary Al, and a positive association between the variability (standard deviation) of visual reaction times and exposure (based on serum Al). Low scores for the combined symptoms and mood scores were associated with a high serum Al (S-Al) (fatigue, memory, depression or tension or irritability). In the QEEG, the amount of delta and theta activity in the frontal region correlated positively and the amount of alpha activity in the frontal region correlated negatively with S-Al.

The authors noted that because of the small sample size, the statistical significance of the exposure-effect associations for the neuropsychological tests was modest and the "results are only suggestive". However the type of neuropsychological impairment is consistent with previous documentation seen in workers exposed to Al in other (nonwelding) settings (Hosovoski et al, 1990; White et al, 1992) which will not be reviewed here. The negative association between mood disturbance and S-Al was contrary to expectation and difficult to explain. EEG abnormalities have been found among patients with dialysis encephalopathy. The authors noted that as far as they were aware, no studies had been published concerning EEG findings from occupationally exposed subjects with normal renal function. In the present study, welders with higher levels of S-Al had more slow (delta and theta) activity and less alpha activity in the frontal areas compared with welders with lower levels of S-Al. They felt that these results were "principally consistent" with the findings from patients with Al encephalopathy and from animal experiments, and suggested that Al uptake from welding may have an effect on cerebral function. They noted that their study "does not allow any definitive conclusions" but that Al welding may involve hazards for the CNS, with disturbances of memory and attention possibly the most likely early effects.

A recent U.S. case-control study involving cases of amyotrophic lateral sclerosis and controls with other neuromuscular disorders and from the community (Strickland et al, 1996), found the strongest association with welding or soldering, OR 5.3 (95% CI 1.4-20.1). The authors wondered whether lead might be responsible.

Summary: The findings to date remain limited, in large part, to associations with neuropsychological symptoms. Further confirmation with objective neuropsychological tests is required. It is possible that any effects, if they exist, may be due to metals including Al or lead which are seen in other occupational (nonwelding) settings.

5.2 Renal Effects

1985 Review: The limited studies available at that time did not permit one to conclude that renal impairment occurred as a result of welding.

Recent findings: A case-control study of severe renal disease and glomerulonephritis cases and population-based referents matched by sex, age and community in Sweden (Hagberg et al, 1986) assessed exposure to welding fume by means of a questionnaire. There were no differences in exposure to welding between cases and referents, with rate ratios for all welding fume of 0.94; for welding fumes more than 100 days per year of 1.53 (95% CI 0.4-1.9), for SS welding of 0.83, and for welder given as occupation of 0.82.

Verschoor et al (1988) examined the influence of occupational exposure to water-soluble chromium (VI) on renal function in chrome platers, SS welders, boilermakers and a control group of workers in the Netherlands. The serum creatinine was significantly higher among the welders than the other groups, and the combined Cr(VI) group (chrome platers and welders) had some differences in glomerular function parameters compared with the Cr-dust or non-exposed group (boilermakers and controls) but the renal function parameters were not related to chromium concentration in the urine or to chromium clearance. The authors concluded that some evidence for alterations in glomerular function was observed in chrome-plating workers and welders which "may be caused by exposure to Cr(VI)" but that it is also possible that other characteristics such as a static workload may be causal factors. It was difficult to find relationships between exposure and renal function parameters.

Subsequently, Vyskocil et al (1992) examined biochemical markers of kidney damage in 52 male SS (MMA) welders exposed to chromium and nickel and matched referents. The prevalence of abnormal values in the welders did not differ from that in the controls and no consistent or clinically significant renal impairment was observed among the SS welders exposed to chromium air concentrations slightly above the current ACGIH TLV for water-soluble Cr(VI) of 50 µg/m³.

Very recently, however, a Belgian study (Nuyts et al, 1995) examined occupational risk factors for chronic renal failure (CRF). Cases of CRF were identified from five renal units interviewed within six months of the start of their dialysis therapy, and controls were people with normal renal function randomly selected from lists of voters in the same communities. A structured questionnaire was used to obtain information on lifestyle characteristics (smoking, drinking and medication intake), medical history, and occupational history. A significant increased risk of CRF was found for welding fumes (OR 2.06, 95% CI 1.05-4.04). However, there was no exposure trend suggestive of a dose-response relation.

Studies of welders and brazers (Elinder et al, 1985a,b) who have exposure to cadmium in solders have shown tubular damage with various markers such as -microglobulinuria, similar to what has been demonstrated with cadmium exposure in other settings.

Summary: Most of the new studies available provide little evidence for renal function abnormalities among welders as a group or SS welders exposed to water-soluble Cr. However, one recent study from Belgium found an increased risk of CRF for welding fume, although no trend with exposure was observed. Welders with cadmium exposure may have changes that had been observed for many years among groups with exposure to cadmium in other settings.

5.3 Skin Effects

Kanerva et al (1991) reported from Finland a repeated urticarial reaction associated with fever occurring in a welder while welding steel profiles filled with polyurethane. Provocation tests with two pyrolysis products (4,4'-diphenylmethane diisocyanate and 4,4'-diaminodiphenylmethane) were negative.

5.4 Reproductive Effects

5.4.1 Effects on Semen and Subfertility

1985 Review: Rachootin and Olsen (1983) compared infertile couples (cases) with fertile couples (referents) and obtained information on occupational exposures by postal questionnaires completed by the women (response rate 87%). They focused on exposures preceding hospital care for either infertility or childbirth. Welding on SS but not on other types of steel was associated with reduced sperm quality (deterioration in concentration, motility or morphology). However, in an internal analysis among the case group, there was no difference in welding exposure among cases of idiopathic origin and cases with urogenital disorders. Moreover, in an internal analysis among the referents, welding of other metals but not SS welding was associated with delayed conception. Thus, the results were not entirely consistent as an association was found between SS welding and reduced semen quality, but not with delay of conception, and conversely, between non-SS welding and delay of conception but not with reduced semen quality. This 1983 report was described by Bonde (1993) as an hypothesis-generating study. In animal studies, high doses of hexavalent chromium cause testicular atrophy and decreased sperm count.

Recent findings: Most of the recent reports have been published by one investigator (J.P. Bonde) from Denmark. Mortensen (1988) reported the findings of a case-referent study involving 3,119 men who had delivered semen sample(s) to one of three hospitals in Denmark in connection with fertility problems. A mail questionnaire was sent to the men with an 81% response rate. The sperm samples of the men were categorized according to sperm concentration, motility and appearance; if any of the criteria were abnormal, the sperm quality was considered to be poor and the man was classified as a "case". The questionnaire information was used to categorize the men as (i) welders; (ii) metal workers not exposed to welding; (iii) other industrial workers; and (iv) unexposed workers. After adjusting for confounders, there was an increased risk for reduced sperm quality among welders compared to unexposed workers (OR 2.0 (95% CI 1.2-3.4)) but not in the other groups. This was concentrated among those working on SS (OR 2.3).

On the other hand, Jelnes and Knudsen (1988) examined sperm quality among 145 men, representing 64% of the eligible workers. The subjects included 77 SS welders and 68 age- and smoking-matched referents, who were mostly but not exclusively from the same plants as the welders. There were no differences in semen quality parameters between the welders and nonwelders. This study was limited by selection bias (the low participation) and because hexavalent Cr exposures were lower than in other studies. Additional comparisons of a sample of 20 welders to external controls also did not show differences between the groups. The authors concluded that the data suggested that SS welding did not present a major risk of reduced semen quality.

In a cross-sectional study, Bonde (1990) examined semen quality in 35 SS welders using TIG, 46 MS welders using MMA and MAG, and 54 nonwelding metalworkers and electricians (participation rates of 37% in welders and nonwelders). They were asked to deliver three semen samples at monthly intervals, and these were provided by 27, 46 and 35 of the subjects, respectively, with mean values used for those providing multiple samples. The referents were selected from the same geographical, occupational and social setting as the welders, and were similar in age and smoking but differed in alcohol and bathing. There were no differences between MS or SS welders in sperm concentration, proportion with low concentrations (<20 million), or proportion with <50% normal morphology. The sperm count per ejaculate, the proportion with normal morphology, the degree of sperm motility, and the linear penetration rate of the sperm were significantly decreased in the MS welders. A dose-response relation across high and low MS exposure and referents was observed for these parameters (sperm count excepted), with semen quality decreasing and FSH concentrations increasing with increasing exposure. For SS welders, total sperm count per ejaculate, proportion of motile sperm, motility, and concentration of testosterone were also decreased. Selection bias was possible due to the low participation rate. Based on an initial questionnaire (with 80% response rate), previous knowledge of reduced semen quality and history of urogenital disorder was more prevalent among participating referents than non-participating referents but not among welders, suggesting that bias towards the null hypothesis was possible. The results concerning the MS welders with dose-response and consistency of sperm and FSH findings were felt to add to the reliability of the findings but those for SS welding were considered "more dubious".

Bonde and Ernst (1992) did not find that semen parameters deteriorated with increasing level of internal exposure to chromium among 30 TIG/SS, 30 MS welders and 47 non-welding workers in Denmark, and concluded that low-level exposure to hexavalent chromium in these welding groups did not appear to be a major hazard for human spermatogenesis.

A longitudinal design was adopted (Bonde, 1990a) to deal with the methodological drawbacks of cross-sectional studies. The analysis was designed to detect changes in semen parameters in the postvacation relative to the prevacation period among subjects in the previous study (of whom 19 MS welders, 18 SS welders and 16 referents participated). The participants were asked to deliver subsequent semen samples 3, 5 and 8 weeks after the last day of summer vacation. No significant improvement relative to the prevacation level was observed for any semen parameter among the welders during the follow-up. Contrary to expectation, among the non-exposed referents but not among welders, there was a significant time-dependent increase in sperm concentration and the proportion of normal sperm forms during follow-up, which could not be explained by sexual abstinence, urogenital infection, or fever in the preceding three months. The author hypothesized that this difference might be interpreted to be the result of a "vacation effect" improving the semen quality among non-exposed subjects but not among welders because of a lasting suppression of spermatogenesis by welding exposure (i.e. that the effect of welding is non-reversible within the rather short period of non-exposure), or alternatively, that the reported associations between exposure to welding and poor semen quality are of a non-causal nature.

A case-referent study within a cross-sectional sample was conducted among workers at six workplaces in Denmark (Bonde, 1990b). Delayed conception was defined by questionnaire as "have you and your wife (former or current) ever had difficulties in conceiving? - Only answer YES if you have tried at least two years without success (no pregnancy)". An association with welding exposure at the time of delayed conception was observed (OR 2.2 (95% CI 1.1-4.6)); when adjusted for confounders the risk dropped to 1.9 (0.8-4.1). When exposure was classified according to exposure at the time of case/ birth, welding was associated with delayed conception (OR 1.9 (0.99-3.59)) and this remained unchanged after adjustment for confounders (OR 2.0 (1.0-4.0)). Such studies are susceptible to various biases including recall bias.

Bonde et al (1990), as part of a large study of 10,059 production workers described below (Bonde et al, 1992), examined the relationship between fertility and welding exposure in a cohort of Danish male metalworkers. The occurrence of a birth in a given year was analyzed by logistic regression conditional on exposure (welding or not, MS or SS) during the preceding year as well as on several potentially confounding factors, including age, birth cohort, paternal parity, birth of a child in the preceding five years, smoking and alcohol consumption. The probability of a birth in years at risk from welding exposure was slightly but significantly reduced (OR 0.89, 95% CI 0.83-0.97). When examined according to MS or SS welding, MS welders experienced a significantly reduced likelihood of having a child during years at risk from welding (OR 0.86, 95% CI 0.76-0.99) but SS welders did not (OR 0.98, 95% CI 0.84-1.31). Among SS welders (after excluding years of MS welding), there was no difference in fertility between the not-at-risk years before and after welding (OR 0.96) nor was fertility decreased during years at risk from exposure (OR 0.95). Among never welders, the fertility of SS grinders who also have chromium and nickel exposure, was similar during years with and without exposure risk (OR 1.0). The authors noted that the effect associated with MS welding, although a small decrement, was similar to the effects in other studies of conception delay (Rachootin et al, 1983; Bonde, 1990b) and of reduced semen quality (Mortensen, 1988). It should be noted, however, that the small effects could be due to uncontrolled confounding, and that there was no trend in fertility with duration of welding exposure or with time elapsed since last exposure. The authors suggested that additional investigations are needed before a clear picture will emerge.

Radiant heat: Bonde (1992) investigated whether semen quality was affected before, during and after exposure to radiant heat in 17 MMA welders working on alloyed steel compared with two reference groups (54 nonwelding metal workers, with participation rate 37% and 19 flexoprinters, with participation rate 91%). The semen samples were examined blindly. For sperm samples delivered during exposure, the mean total sperm counts were lower in the welders (of borderline statistical significance) but no statistical differences were observed for motile sperm count, sperm concentration, proportion with normal morphology, and proportion motile. Prospective examination among the welders showed that sperm count, motile sperm count, sperm concentration and proportion of normal shaped sperm decreased within 4 to 6 weeks of the onset of exposure to heat in a subgroup of 10 welders, and then increased 4 weeks after cessation of heat exposure in a subgroup of 8 welders. There was a significant difference (p<0.01) in the proportions of sperm with normal shape found between the start of exposure (within 2 weeks) and during exposure (4 to 8 weeks), and between exposure (12 to 32 weeks) and after vacation. During exposure to heat, the skin temperature in the groin increased on average by 1.4°C.

5.4.2 Other adverse reproductive outcomes: Bonde et al (1992) conducted a large pregnancy outcome study among children of a cohort of fathers (drawn from 10,059 male metal workers employed at Danish SS or MS manufacturing companies for a minimum one year during 1964 to 1984), created from records in the Danish Pension Fund. Data on job title and department of potential cohort members were obtained at each of the 79 companies by standard interviews with managers, foremen and long-term workers. Only subjects with verified employment as MS welders, SS welders, SS grinders, or nonwelding and nongrinding production workers were admitted into the cohort. During 1986, cohort members were mailed a questionnaire on lifetime occupational exposures and smoking and drinking habits, with an 85% response rate. Liveborn offspring of all cohort members were identified from records in the Danish Central Population Register. There was a total of 3569 children fathered during the time period. The occurrence of low birthweight, preterm delivery, infant mortality and congenital malformations was not increased among children at risk from parental welding exposure compared with children not at risk. The risk of spontaneous abortion (SA) in previous pregnancies was moderately increased for pregnancies at risk from paternal exposure to SS welding (adjusted OR 2.0, 95% CI 1.1-3.5) but not from MS welding (OR 1.1, 95% CI 0.5-2.4). The risk was somewhat higher for pregnancies at risk from MMA/SS welding where Cr exposures were higher (OR 2.0) than from TIG/SS welding (OR 1.7) but the confidence intervals overlapped. The number of years with paternal SS welding experience did not influence the rate of SA.

However, there were several design limitations. First, the occurrence of SAs was monitored conditional on a subsequent birth. If SS welding has a strong effect on abortion rate, a relatively smaller fraction of pregnancies proceed to birth, which might lead to an underestimation of risk. On the other hand, women experiencing a SA might be expected to become pregnant again sooner. Second, the frequency of SAs was distorted by a high frequency of induced abortions. Third, the risk estimates were blurred by misclassification of exposure (with no data on the actual date of the SA preceding the index birth). An analysis undertaken including only births with either exposure or non-exposure through all three years preceding the birth resulted in a risk estimate for SA among SS welders that was unchanged (OR 1.7, 95% CI 0.9-3.1). The authors felt that recall bias could be excluded because the data on occupational exposure had been collected prior to the planning of the study and information on outcome variables was obtained independently. Differences between wives of the various groups of metal workers were possible; although only limited data were available, there were not expected to be major differences. The authors concluded that the hypothesis of SA increases among SS welders should be tested in further studies.

In contrast to this Danish study, Lindbohm et al (1991) investigated parental exposure and SAs in Finland by linking a nationwide data base of medically diagnosed SAs with national census data. The risk of SA was not increased in a number of parental exposure categories, including metals (OR 1.0, 95% CI 0.8-1.1).

5.4.3 Cancer in Offspring: Bunin et al (1989) explored multiple parental occupations among cases of Wilms' tumour and controls selected through random digit dialing in the U.S. using a matched case-control design. The only significant findings were linked to aromatic hydrocarbons, aliphatic hydrocarbons, metals and inorganic compounds. Welding among fathers was reported among 5 cases but only 1 control. One previous study (Kantor et al, 1979) also demonstrated this association. A similarly designed study of retinoblastoma by these investigators (Bunin et al, 1990), found an association with parental employment in the metal industry for the sporadic heritable form (OR (95% CI 1.4- ; p=0.02)) but this was not significant among welders and machinists (OR 2.3 (0.5-14)). For the nonheritable form of retinoblastoma, a significant association was observed for the job cluster consisting mostly of welders and machinists (OR 4.0 (1.1-22.1; p=0.04)).

In the follow-up study of reproductive end points among metal workers noted above, Bonde et al (1992) found that the overall incidence of childhood malignancies among 23,264 children born to the 10,059 metal workers was equal to national rates (relative risk 0.97) and was even lower among children of MS welders (0.93) or SS welders (0.77).

Summary: Bonde (1993) presented an overview of these various reproductive outcomes attributable to welding of metals, noting that hexavalent chromium and perhaps also manganese might be toxicants of interest. He noted that the internal load of these metals following short-term welding is probably "rather low in comparison with the lowest observed spermatotoxic effect levels found in animal experiments". Overall, some (Mortensen, 1988; Bonde, 1990b) but not most studies found deterioration in semen quality and fertility in welders. However, the inconsistencies between studies have not been explained and problems in methodology, low response rate, possible recall bias and so on, have to be considered, as well as the possibility that the observed associations are "of a non-causal nature" (Bonde, 1993). The evidence for a relation of welding exposure to SA (and congenital anomalies) is inadequate to reach conclusions. There is limited evidence that the risk of Wilms' tumour (and possibly retinoblastoma) is increased among the offspring of welders.

5.5 Mutagenesis

5.5.1 In vitro studies

The basis for these investigations includes that welders are exposed to and absorb chromium and nickel compounds, and that chromium and nickel in other settings are recognized to be human carcinogens by inhalation (IARC, 1990).

1985 Review: Studies reviewed 10 years ago indicated that SS welding fume appeared to be mutagenic (genotoxic) in bacteria and in cultured mammalian cells, that hexavalent chromium compounds might constitute the active component, and that gas shielded welding (MIG) produces much less hexavalent chromium than MMA.

Recent findings: Studies published during the recent period are consistent with this. Hansen and Stern (1985) showed that in the baby hamster kidney (BHK) transformation test and in primary Syrian Hamster Embryo cells, fumes from MMA/SS had transforming effects attributable to the Cr(VI) content. MIG/SS and MMA/MS had only small effects even at relatively high doses but neither contain appreciable amounts of Cr(VI). The fumes from MIG/SS had a toxic effect but this was 2-3 times greater than expected from their soluble Cr(VI) content. Relatively insoluble Cr(VI) compounds in this fume showed a higher toxic and transforming effect in the BHK assay than could be ascribed to the soluble Cr(VI) content of the medium, indicating the importance of phagocytosis as a pathway for uptake of Cr(VI) and other toxic substances from particulate.

Reuzel et al (1986) found positive results in the Ames assay and for sister chromatid exchanges (SCEs) for MMA/SS welding fume but negative results in the HGPRT test and in a DNA repair test in human cells (unscheduled DNA synthesis). The findings were similar to those of K₂CrO₄, if compared on the basis of soluble chromium quantities. Baker et al (1986) examined the effects of soluble and insoluble fractions of welding fume generated from MMA in inducing mitotic delay and SCEs in cultured Chinese hamster lung cells. They found that the water-soluble and water-insoluble fractions induced SCEs in proportion to their Cr(VI) content, while the contribution from other elements was minimal. However, mitotic delay could not be explained by Cr(VI) concentration alone, suggesting that other components of the fractions were capable of inducing mitotic delay. The activity of the insoluble fume fraction in both tests was markedly less than that of the soluble fraction, attributed to the lower bioavailability of "insoluble" components of the fume particles.

Biggart et al (1987) noted that in past studies using the modified Salmonella/ microsome assay, particles from welding SS containing 15-25% chromium were mutagenic and MS particles containing 0.1% chromium were not mutagenic or toxic. However, these investigators showed that MS welding fume induced a dose-dependent increase in reversions with or without S9 mix in the assay; thus MS particles were thought to contain direct-acting and promutagenic compounds that induced frameshift mutations, but not base-pair substitutions. The chemical nature of the mutagenic compounds was investigated. Because the mutagenicity and toxicity of the particles could not be recovered in the filtrate from particle suspension, the agents were not water soluble, and did not contain chromium compounds. Moreover, other studies indicated that an ionic metal species was not released from the particles. They felt that this demonstration of mutagenic activity in welding fume particles was an important factor to consider in assessing the potential toxicity and carcinogenicity of welding fumes.

De Raat and Bakker (1988) examined the induction of SCEs in Chinese hamster ovary cells from different welding fume processes. MMA/SS fume induced the greatest amount of SCEs, while doses about 100 times higher were required to produce effects with particles from MMA cast-iron, MIG/SS and MMA/MS, while no significant induction of SCE was demonstrated with MIG/MS. The effects could be explained by soluble chromium only for MMA/SS, while the effects associated with MMA/Cast Iron and MIG/SS particles may be caused by insoluble chromium and/ or nickel, as previously suggested. While MMA/MS particles contain some soluble chromium, the amount was not great enough to explain the effects, and no explanation for the induction of SCEs by these particles was available.

5.5.2 Cytogenicity Studies in Welders

1985 Review: Two studies performed before 1985 (Husgafvel-Pursiainen et al, 1982; Littorin et al, 1983) did not show chromosomal changes in lymphocytes of welders.

Recent findings: Elias et al (1989) studied chromosomal aberrations in France among 55 controls and 55 welders (22 MMA on coated electrodes - usually MS but SS occasionally used; 18 welders using semi-automatic MAG on nickel wire with MS metal, exposed to iron, manganese and nickel; and 15 welders using semi-automatic TIG for SS wires). The frequencies of cells with aberrations and of total structural chromosomal aberrations in welders was significantly greater (P<0.001) than in the non-exposed controls, mainly attributable to a higher frequency of chromosomal gaps in welders. In the second group of welders (MAG/Ni), the proportion of total aberrations as well as cells with aberrations was significantly higher than matched controls (P<0.01, gaps included and P<0.05, gaps excluded). In this group, there was a significant correlation between length of welding employment and frequencies of breaks, both chromatid and chromosomal (although multivariate control for smoking was not conducted). Smoking habits had no effect on the incidence of gaps but induced increased chromatid and chromosome-type breaks, acentric fragments, and in welders only, the exchange type aberrations. The authors concluded that certain welding processes may generate fumes that seem to have clastogenic activity; it was detected in a group of welders not usually welding SS who were exposed to nickel, from welding wire.

Popp et al (1991) from Germany investigated the frequencies of chromosomal breakage, cross-linking and SCEs in lymphocytes of 39 welders engaged in MAG and MMA welding using Cr/ Ni/ Mn electrodes on low- to medium-alloy steel and a control group of 18 nonexposed men whose smoking habits and age distribution (35, 36-45, 46) were standardized to the exposed group. The average SCE frequency for welders was significantly lower (P<0.05, Wilcoxon test) than that for the control group, consistent with the findings of Littorin et al (1983) and Husgafvel-Pursiainen et al (1982). The SCE frequency was raised among smokers in both groups, as expected, but the differences were not significant. However, among the welders, the SCE frequency and frequency of DNA strand breakage was significantly (P<0.05) correlated with the chromium concentration in the urine. These investigators also found a reduced frequency of strand breakage and increased frequency of protein cross-linking in the welders (as measured by reduced elution rate through filters). The authors explained this as follows: if one assumes a high proportion of DNA-protein cross-links in welders, then the reduced elution rate through polycarbonate (PC) filters can be explained in terms of a relative reduction in the numbers of shorter DNA fragments, which are partially cross-linked to protein and therefore cannot pass through PC filters. It is known that chromium can cause the formation of DNA-protein cross-links that remain stable, whereas chromium-induced DNA single-strand breaks are rapidly repaired. Thus, the main carcinogenic effect of chromates is now attributed to DNA-protein cross-link formation (Popp et al, 1991). The authors therefore concluded that the present results were in good agreement with in vitro and in vivo investigations confirming the importance of DNA-protein cross-links for the carcinogenic effect of chromium.

Knudsen et al (1992) examined various measures of genotoxic exposures in peripheral lymphocytes among 127 SS welders from 15 work places in the metal industry in Denmark (63 MMA and TIG, 52 predominantly TIG, and 12 predominantly MIG) compared with referents involved in cutting, repair work and administrative work at the same workplaces as the welders. Results were tabulated separately according to smoking status. The welders had an increased frequency of chromosomal aberrations, especially those involved with MMA welding which generates a higher chromate content in fume and greater urinary chromium. There was a decrease in unscheduled DNA synthesis and in SCE exchanges among welders. This is consistent with the previous studies which did not show significant differences in this latter outcome (Husgafvel-Pursiainen et al, 1982; Litorrin et al, 1983).

Costa et al (1993) in the U.S. used a new method for detecting DNA-protein cross-links in peripheral white blood cells among 21 railroad arc welders exposed to MS fume (none were exposed to SS welding recently) and 26 unexposed controls who were office workers, field railroad workers in supervisory positions, union representatives, janitors and laboratory technicians. The distribution of levels of DNA-protein cross-links in the two groups overlapped; however the levels were higher among the welders (mean ± SD, 1.85±1.14%) than among the controls (1.17±0.46%) (p=0.01). Of the 21 welders, 5 (24%) showed cross-link values above 2.33%, which was the upper range of the controls. Cross-link values did not vary according to age, smoking status, body weight, or race. The Ni levels in blood were not elevated in welders and there was only a slight elevation of Cr levels. Despite the observed increased in cross-linking, the authors were unsure of the agent involved. They concluded that welders were burdened with an excess of DNA-protein cross-links in cells indicating not only a biomarker of possible exposure to cross-linking agents (i.e. nickel and chromium) but also the presence of a lesion that may be an early indicator of other potential genotoxic consequences (cancer).

Jelmert et al (1994) in Norway examined chromosome damage in lymphocytes from 42 MMA/SS welders (defined as using MMA/SS for more than two-thirds of active welding time), and a subgroup of 20 SS welders studied before starting MMA/SS welding and retested after 1-4 months of welding. For each welder, a referent subject matched for gender, age and smoking habit was selected among office workers or other subjects not exposed to welding fume (reference group I), of whom 2 had unsuccessful cultures yielding 40 referents. These referents were also included within another reference group (reference group II), comprising 91 office workers, one gardener and two scaffolders. There was a significant increase among welders in chromatid breaks (1.4 vs 0.9 and 0.8 for groups I and II, respectively) and for cells with aberrations (2.2 vs 1.6 in group II). In the SCE assay, the MMA/SS welders showed no increase compared to referents. In smoking-specific analyses, in conventional cultures, a statistically significant increase in the number of chromatid breaks was observed only among non-smoking MMA/SS welders vs referents in Group I (1.5 vs 0.7, p=0.007) and Group II (1.5 vs 0.7, p=0.0009). There were no differences in smoking-specific strata for SCEs. No synergistic effect between smoking and welding fumes was observed for any type of aberration. The results indicated that the increase in chromatid breaks was associated with cumulated welding fume exposure for more than a year, and with not using any type of respirator, but not with current welding fume exposure during the week before sampling. For the subgroup of 20 welders analyzed for cytogenetic endpoints before and 1-4 months after MMA/SS welding, there was a significant increase found for chromatid breaks. However, compared to their matched referents after welding, there was no increase observed. The authors offered possible explanations for the inconsistency (and confusing findings) with the matched referents: that there were difficulties in selecting reference groups; alternatively, individual variation in results of repeated cytogenetic analyses could not be completely excluded. The authors noted that in two of the three previous non-positive studies, there were non-significant increases. The authors concluded that the small but statistically significant increase in chromatid breaks, but not in other types of chromosomal aberrations, observed for MMA/SS welders compared to matched referents, or with the results for the same welders prior to exposure, suggests that MMA/SS welders are exposed to cytotoxic agents capable of inducing chromatid breaks.

In a subsequent report from this group (Jelmert et al, 1995), the authors did not find evidence of cytogenetic damage among TIG/SS or MIG/MAG/SS welders, exposed to fumes containing a relatively lower content of Cr and Ni than the MMA/SS fume studied in the previous report. The fact that these welders are exposed to several of the same agents as the MMA/SS welders (ozone, NO_x, electromagnetic fields and ultraviolet light) but did not have aberrations, suggests that these common exposures were unlikely to be responsible for the increase in aberrations in the MMA/SS welders.

Summary : During the recent time period, although lymphocytes of welders again have been found not to demonstrate increases in SCEs, several studies have demonstrated genotoxic effects on lymphocytes of MMA/SS welders, mainly with respect to chromosomal aberrations (and DNA-protein cross-linking). This represents a new finding not seen in the earlier time period. However, the implications of the findings concerning these markers of genotoxicity are uncertain at present.

6.0 CANCER

6.1 Lung Cancer

Because of the presence of potential carcinogens in welding fume, and the respirable nature of the fume, it is to be expected that attention should be paid to the possible risks of respiratory cancer among welders.

1985 Report: In my previous document, it was noted that the studies published through 1984 were consistent in suggesting a relative risk (RR) for lung cancer among welders of about 1.3 or 1.4; almost all of these concerned MS welders (or welders in general) rather than SS welders specifically. The study by Sjogren (1980) was the only cohort of SS welders published up to that time (three welders died from pulmonary tumours, SMR 441, p=0.03). Several explanations for this increase in welders have been discussed (Liss, 1985; Peto, 1986). The first possibility was that the risk is negligible and the confounding effects of smoking (and perhaps exposure to other occupational carcinogens) could account for the results. The second possible explanation was that MS welding involves little or no risk but that exposure to certain welding processes, in particular SS welding, constitutes a "hot spot" (Stern, 1983a,b) (i.e. a higher risk of lung cancer), given that there is exposure to hexavalent Cr, that SS welders absorb Cr, that SS welding fumes are mutagenic in vitro, and that chromates have been demonstrated to be carcinogenic in other industrial sectors. The third possible explanation was that long-term employment as a welder of any type may cause a substantial increase in lung cancer after a sufficient latency period has elapsed (e.g. Beaumont and Weiss, 1981).

Commenting on the inability to sort out these possible factors, (Peto, 1986) called for further studies based on pooling data from established cohorts. Similarly, Stern et al (1986) noted that the available evidence did not indicate conclusively among the above possibilities, and noted that "retrospective cohort studies of both stainless steel and other welders who have been exposed for many years and followed up for at least 20 years are therefore urgently needed." What new light has been shed on this question in the past decade?

Recent findings:

6.1.1 Animal carcinogenicity studies: Reuzel et al (1986) administered 2.0 mg MIG/SS or 0.5 or 2.0 mg MMA/SS fume, saline or calcium chromate by intratracheal installation to 35 male Syrian golden hamsters per group, weekly for 56 weeks (except high dose MMA/SS which was reduced to monthly). One animal in the 2.0 mg MMA/SS group developed a well-differentiated combined epidermoid and adenocarcinoma of the lung, and one animal in the 0.5 mg MMA/SS group showed an anaplastic tumour in the lung, with no tumours in the other groups. Berg et al (1987) implanted pellets of MMA/SS fume or thermal fume spray containing chromic oxide (III) and (VI) in the bronchi of 100 male and female Sprague-Dawley rats for 34 months, along with negative and positive (benz(a)pyrene) controls. One rat receiving a welding fume pellet developed squamous cell carcinoma remote from the implantation site "with no apparent relation to the bronchus", (i.e. considered to be unrelated to the treatment); the positive controls developed tumours. IARC (1990) considered that there was inadequate evidence in experimental animals for the carcinogenicity of welding fumes. I do not know why there are no inhalation studies in rodents.

6.1.2 Studies in Humans

First the available cohort studies are considered, including a rating of study methodology or quality. Next, the results of the case-control studies of lung cancer which comment on welders are tabulated, although these studies were not necessarily designed specifically to examine this question in particular. Third, we attempt to interpret the data, taking into account criteria for causality, including evidence regarding the two confounding factors most frequently noted: smoking among welders, and evidence for asbestos exposure.

6.1.2.1 Cohort Studies

There were 10 cohort studies published since 1985 that were identified; all were from Europe except one from the U.S. (Steenland, 1991). Table 5 summarizes the features of the studies. The studies by Becker et al (1989) and by Sjogren (1987) are updates of earlier studies published in 1985 and 1980, respectively, that were included in my 1985 review. One study (Sjogren and Carstensen, 1986) was based on linkage of the national census to a cancer register; the others were cohort incidence or mortality follow-up studies of specifically enumerated and traced populations. The table includes the international European collaborative study by IARC (Simonato et al, 1991), which is the largest study and constitutes what is closest to a "meta-analysis". It includes subjects with overlap from separate studies conducted in Germany (Becker, 1989), Sweden (Sjogren, 1987), Finland (Tola, 1988), Norway (Mekild, 1989) and France (Moulin, 1993).

Validity Assessment: The findings of the validity assessment of the methodology of the studies are summarized in Table 6. The kappa for interobserver rating was 0.53, indicating moderate agreement. The ranking varied from 25 to 37 out of 42, with median rank about 33. In general the quality of the studies was quite good, with the lowest ranking for the census study by Sjogren and Carstensen (1986); the study by Steenland et al (1991) was rated the highest.

Cohort Study Findings (Table 7)

6.1.2.1.1 Mild Steel Welders

Studies of MS welders are presented separately for shipyard and nonshipyard subjects. The one census study of welders (Sjogren and Carstensen, 1986) showed a 42% increase in lung cancer mortality.

Shipyard:

External comparisons: Of the five separate studies reporting on shipyard welders, in which exposure to asbestos has been considered to be somewhat more likely, four (Newhouse, 1985; Tola, 1988; Mekild, 1989; and Danielsen, 1993) showed excess lung cancer SMRs or SIRs of varying magnitude, ranging from 113 to 250, and in one (Moulin, 1993), deaths from lung cancer were slightly less than expected but this was based on only 3 deaths. Only the study by Danielsen et al (1993) was "statistical significant" on its own (although this is not of primary concern). Combined, these five studies had a pooled SMR of 127 (95% CI 100-160; p=0.03), identical to the SMR of 126 (95% CI 88-174) observed among shipyard welders in the IARC study (Simonato et al, 1991).

Dose-response: Danielsen et al (1993) provided evidence of a "dose-response" relationship with somewhat higher risk among those employed for more than 3 or 5 years, with the SMR reaching 400 among those with 5 years exposure (Table 7), although this study was very small with fewer than 4 expected lung cancer deaths. Most other studies had too few cases to examine duration of exposure. Mekild (1989) attempted such an analysis; 5 of the 7 lung cancer cases occurred in the 1-5 years rather than > 5 years duration category, and thus failed to find evidence of a dose-response relation. Simonato (1991) found no association with cumulative exposure.

Latency: There was a moderate latency effect demonstrated by Danielsen (1993), with the SMR increasing to 308 after 15 years latency. Simonato (1991), however, failed to show an increased risk among shipyard welders with less than 20 years since first exposure (YSFE) compared to greater than 20 YSFE.

Internal comparison: Only Danielsen (1993) presented internal comparisons for shipyard welders alone; the authors found RRs of 1.7 for those employed less than 5 years and 3.0 (95% CI 1.3-6.9) for greater than 5 years, which were similar with or without lagging, again based on very few cases.

Nonshipyard:

Three studies presented separate findings for nonshipyard MS welders. Steenland et al (1991), the study in which subjects may have been the least likely to have been "contaminated" with asbestos exposure, showed no excess in lung cancer (SMR 107, 39 deaths), no trend with duration of exposure, and RRs of less than 1 in internal comparisons. This study was rated as the highest in quality. On the other hand, both Tola (1988) (SMR of 142 among machine shop welders) and Moulin (SMR of 160 among "mild steel" welders), reported nonsignificant excess lung cancer for nonshipyard welders, but these were based on only 14 and 9 cases, respectively. Moulin (1993) presented some evidence of a dose-response relation in this group (Table 7). The pooled SMR for these three studies was 119 (95% CI 91-153, p=0.1). In the IARC study, MS welders in factories had a significantly increased SMR of 178 (95% CI 127-243), and the risk increased after 20 YSFE.

Internal comparison: For the entire study (mostly mild steel), Moulin et al (1993) reported a RR of 1.29 (no CI given) which was similar to the ratio of SMRs of 1.32. On the other hand, as noted, Steenland's internal analysis was "nonpositive" based on larger numbers, and was thus inconsistent with the other reports.

6.1.2.1.2 Stainless Steel Welders

The results were not consistent across the three separate studies of SS welders available but these involved very small groups. Sjogren (1987) found a striking excess, SMR 249 (and RR in internal comparison of 4.95), based on 5 cases only. In the recent follow-up period since the initial 1980 report by Sjogren, there were 2 observed vs 1.1 expected lung tumours. In contrast, Becker (1989) found only a small nonsignificant increase in the external comparison of SS welders (SMR 113; with SMR of 109 for the nonwelding comparison group of turners), and a RR of 1.2 in the internal comparison between the welders and turners. Moulin (1993) found no increase among ever SS welders (SMR 92) or predominantly SS welders (SMR 103) but these were based on 3 and 2 observed cases, respectively. Combining these 3 studies yielded a pooled SMR of 124 (95% CI 78-188; p=0.18).

In the IARC study, Simonato (1991) reported SMRs of 128 and 123, respectively, among ever and predominantly SS welders, identical to the pooled results. The authors noted that the predominantly SS welders were the group in which they observed the greatest increase across latency categories (SMR 80 for < 20 YSFE, and 177 for 20 YSFE). They considered that this suggested a relation of lung cancer mortality with the occupational environment. However, there was no association with cumulative exposure.

6.1.2.2 Case-Control Studies

There were 12 case-control studies identified, published in 1985 or after, that examined the association between lung cancer and welding. In one of these studies (Silverstein et al, 1985), the job title "maintenance welder or millwright" was considered exposed to coal tar pitch volatiles and welding fume. In my opinion, this study is not informative about welding fume because another carcinogen was part of the case definition. Features of the other studies and whether there was adjustment for smoking are summarized in Table 8.

Of these studies, only one (Hull et al, 1989) was essentially "negative" for most subgroups considered (ORs of 0.6-1.1 for MMA, gas-shielded, SS, high-alloy steel and confined space) although the OR was 1.6 for MS. The ORs in the other studies ranged from 1.1 to over 3.0 (Table 8). Five studies had values with ORs with increased risks in the range of about 40% as had been found in the past: Schoenberg, 1.2 for welder or flame cutter but higher estimates for shipyards or "without reported exposure to asbestos"; Benhamou, 1.4; Jöckel (crude) 1.35; Rinsky 1.1 for possible and 1.5 for potential exposure; Siemiatycki 1.6. The other five studies had higher relative risks (1.9-3.3) (Table 8).

SS exposure: Kjuus et al (1986) found SS welders to have a higher OR than all welders while Hull et al (1989) did not; in fact, they reported no increase at all among SS welders (OR 0.9).

Shipyards/ asbestos exposure: Shipyard welders were found to have lower ORs than all welders and nonshipyard welders by Lerchen et al (1987) but higher risks than welders in general by Schoenberg et al (1986) (3.5 vs 1.2). Hull (1989) reported an OR of 1.4 for welders with asbestos exposure and 1.7 for shipyard welders, similar to that of 1.6 for MS welders. Perhaps the most informative study, Jöckel et al (1994), presented evidence suggesting that asbestos exposure may be more important than welding, and adjusting for asbestos reduced the ORs considerably, from 1.5 to 1.2 for ever/never welding, and 1.6 to 1.3 for ever oxyacetylene or MMA (both not significant). (See section on "Major Confounding Exposures" for further discussion of this issue).

Latency and dose-response: Only one case-control study (Hull, 1989) presented data examining latency effects (among shipyard welders) and found no effect. Dose-response relationships were addressed in only two studies: Jöckel et al (1994) elegantly examined how risk varied with hours of exposure, but failed to demonstrate any relation. Siemiatycki (1991) found identical ORs for "any exposure" and "substantial exposure".

Summary of case-control studies:

Limitations of case-control studies: Many of these studies were not designed with welding in mind, and/ or looked at many occupations or exposures (e.g. Ronco et al, 1988), leading to the possibility of multiple comparisons. Similarly, there is the problem of publication bias: studies that considered many occupations or exposures but did not find increased risks for welding, may not have reported this ("non-positive") outcome separately. Other potential weaknesses of this study design, including possible selection bias or information (recall) bias, have been well described and will not be elaborated here.

Hull et al (1993) concluded that lung cancer risk was associated with smoking and probably with exposure to asbestos in shipyards. Other factors, including welding, may be important but probably because of limited power and reliance on proxy information, they failed to detect other significant risks. However, essentially all the case-control studies reported a positive association between welding and lung cancer of varying magnitude. Thus, as a group, these investigations strengthen the evidence supporting this association.

6.1.2.3 6.1.2.3 Further Discussion of Stainless Steel Welders

Stainless Steel vs Mild Steel Welders within the Same Cohorts: Two studies included MS and SS within the same cohort (Moulin, 1993; Simonato, 1991); in both cases, the SMRs were greater among MS than SS welders. As Moulin (1995) has pointed out, the results of these studies "focused on lung cancer risk due to chromium or nickel exposure do not clearly suggest that the lung cancer risk is higher for stainless steel welders than for mild steel welders". As discussed above, with respect to demonstration of a dose-response relationship, in the studies of SS welders, no association with cumulative exposure or with duration was observed by Simonato (1991); there was some evidence shown by Becker et al (1991); and Sjogren (1987) had too few cases to examine. Moreover, there were no differences between ever and predominantly SS welders in the two studies where examined (Moulin, 1993; Simonato, 1991).

Meta-analysis of SS welders by Sjogren et al (1994) and associated comments: Because individual studies are often limited by low power, it is natural to seek to combine them, as in meta-analyses. SS welding is no exception, in part because of interest in the possible causative role of chromium (and/ or nickel).

Sjogren et al (1994) presented the results of a meta-analysis examining the association of SS welding and the occurrence of lung cancer in five studies. This included two of the cohort studies included reviewed above (Sjogren et al, 1987; and the subcohort of predominantly SS welders reported by Moulin et al (1993) (defined as having more than 70% of welding activities for at least one year was SS welding)). The German cohort study by Becker (1989) was not included, because, according to Sjogren et al (1994), the occurrence of mesotheliomas indicated the presence of asbestos. The large European (IARC) study was not included by Sjogren et al (1994) because some of the subcohorts were included. They also included three case-control studies in their meta-analysis: Gerin et al (1984) in Canada (reviewed in 1985 document); Hansen et al from Denmark (cited by Sjogren et al (1994) as in press); and Kjuus et al (1986) from Norway (reviewed above). The case-control study from Los Angeles by Hull et al (1989) was not included by Sjogren et al (1994) because there was no adjustment for asbestos. The authors attempted to correct the included studies for asbestos exposure and smoking habits. The results of their analysis are shown below:

The authors argued that this meta-analysis "clearly indicates a relation between SS welding fumes and the occurrence of lung cancer, where the two most important confounders, namely smoking habits and asbestos exposure have been taken into account." They further argued that IARC (1990) noted that there is sufficient evidence in humans for the carcinogenicity of hexavalent chromium in the chromate production, chromate pigment production, and chromium plating industries; that the concentration of Cr(VI) in SS welding (0.1-0.3 mg/M³), is similar to that found in some branches of the chromate industry; and that the concentrations of nickel are low. They called on IARC to reconsider its 1990 statement that there is limited evidence in humans for the carcinogenicity of welding fume and gases, as more studies had been published since, citing Moulin et al (1993), and Hansen (apparently in press at that time), and to separate SS welding fumes from other welding fumes.

Moulin (1995) responded to this meta-analysis reported by Sjogren et al (1994). He noted, as I have above, the similar relative risks of lung cancer among MS vs SS welders within the same cohort, and the other studies not included in the meta-analysis (that is, concerns about the representativeness of study selection). In particular, Moulin (1995) pointed out the following:

1. the Danish case-control study (eventually published as Lauritsen and Hansen, 1996) found similar ORs among MS welders (1.65) and SS welders (1.54);
2. the SMR in the French study (Moulin, 1993) was higher for MS welders (159) than for predominantly SS welders (103);
3. in the German study by Becker et al (1991) excluded by Sjogren et al (1994), the RR was only 1.2 in the internal comparison, and SMR 113 in the external comparison;
4. the case-control study by Hull et al (1989) excluded by Sjogren et al (1994) showed ORs of 0.9 (95% CI 0.5-1.8) for SS welders and 1.3 (0.6-2.3) for SS welders predominantly exposed to hexavalent Cr and Ni (MMA welders), whereas it was 1.6 (0.8-3.1) for MS welders;
5. the findings from the IARC study as noted above, provided no consistent difference between MS welders, SMR 178 (127-243), and predominantly SS welders, SMR 123 (75-190).

Moulin (1995) thus concluded that despite the exposure of SS welders to Cr and Ni compounds, the epidemiological findings do not provide clear evidence to suggest that SS welders are at higher risk of lung cancer than MS welders. I agree that the evidence appears to support this statement, although the size of the SS populations studied has generally been small. Similarly, Marini et al (1995), in a recent letter regarding this subject, pointed out that MS welders were at "higher risk of lung cancer than SS welders", and that the SMR among MS welders in the European study, demonstrated about a doubling of risk at 20 YSFE.

Langård (1994) examined this subject and concluded that "at the present time, it does not seem possible to draw firm conclusions on whether the observed excess results from exposure to Ni- and Cr(VI)-compounds in the welding fumes". Langård (1995) also responded to Marini et al (1995), stating that "the issue of concern is whether exposure to asbestos as a confounder plays different roles in the two groups of welders" (MS vs SS), and that "no firm evidence can be found in published papers on documented differences in exposure to asbestos in the two groups". Similarly, with respect to smoking as a confounder, this may play "a possible differential role as a determinant for lung cancer in the two groups. However, as of today, none of the published studies have presented firm evidence that smoking occurs significantly more often in one of the groups of welders than in the other." He agreed with Marini (1995) that "the evidence so far is weak that exposure to hexavalent chromium is a strong determinant of lung cancer among stainless steel welders".

6.1.2.4 The major confounding exposures for welders

Many of the studies reviewed in this report, as in Liss (1985), show that welders have some excess lung cancer mortality. In these studies, the confounders that are repeatedly considered are asbestos exposure and smoking habits. What evidence is there for the presence (and/ or effects) of these factors in the studies reviewed?

Asbestos exposure: Two possible aspects can be considered. First, one can consider whether mesotheliomas were observed in the cohort studies. Mesotheliomas were found among shipyard welders themselves (Newhouse et al, 1995), SS welders (Becker et al, 1989), and in the census linkage of welders in Sweden (Sjogren and Carstensen, 1986). In addition, in three other studies, mesotheliomas were reported among shipyard control workers (Moulin et al, 1993; Mekild et al, 1989; Danielsen et al, 1993) which indicates the presence of asbestos exposure even though none were found among the welders in these studies. No mesotheliomas were reported among the (nonshipyard) SS welders studied by Sjogren et al (1987), while Tola et al (1988) noted that "the fact that the risk of mesothelioma was not increased" among the shipyard welders that they studied "speaks in favour of relatively low exposure to asbestos". Among the (nonshipyard) MS welders studied by Steenland et al (1991), only one mesothelioma was observed, in an individual who had exposure in a prior job, suggesting that this study may have been one of the "cleanest" with respect to asbestos exposure.

Second, Pairon et al (1994) examined the retention of asbestos bodies (ABs) in the lungs of 211 welders for whom a sample (sputum, bronchoalveolar lavage (BAL) fluid, and/ or lung tissue) was sent for analysis by chest physicians during 1988-91 in France. Eighty-two subjects (38.9%) had elevated lung retention of ABs in all samples studied (30% of sputum samples, 40.1% of BAL fluid, and 39.5% of lung tissue samples). The duration of welding activities correlated with the density of ABs in BAL or lung tissue. Only two of the welders were considered to have other occupational exposure to asbestos. The authors concluded that welding activities might produce higher risks of fibrosis and/ or malignant pulmonary diseases.

Summary: There is rather consistent evidence for asbestos exposure in shipyard welders. Consistent with these findings, Jöckel et al (1994) in discussing the welding-lung cancer association, noted that "the occurrence of an unexpectedly high number of mesothelioma cases in some of the cohort studies, however, suggests that part of the excess risk may be due to confounding by asbestos". The proportion of the increased risk which this could explain is not known. However, an interesting analysis according to individual smoking habit was provided by Moulin et al (1993), which illustrates the known synergism (interaction) between asbestos and smoking on the risk of lung cancer. They demonstrated remarkably high SMRs for lung cancer among heavy smokers in shipyards both among welders (SMR 694) and controls (SMR 507), compared to those found for heavy smokers in other factories, where asbestos exposure was less likely, both among welders (SMR 273) and controls (213).

Smoking habits: In my initial review (Liss, 1985), I noted that the estimate of the proportion of welders reported to be current smokers was 22% more than expected in one report (Registrar General, 1978) which one author felt might account for about 37% excess risk for welders in England and Wales (Stern, 1983b). In the cohort studies reviewed here, no information on smoking habit was available for two individual studies (Newhouse, 1985; Mekild, 1989) and for the international IARC study.

Of the studies that provided data on smoking prevalence, Tola (1988) reported that smoking habits were no different than the general population. However, evidence that welders smoke more than the general population was provided from the U.S. (Steenland, 1991), Sweden (Sjogren and Carstensen, 1986 referring to a 1965 survey), France (Moulin et al, 1993), and Norway (Danielsen, 1993). Moreover, Sterling and Weinkam (1976) analyzed smoking habits among various occupations in the U.S. based on the 1970 Household Interview Survey. This indicated that welders had heavier than average smoking habits (52% identified as current smokers, including cigarettes, cigars and pipes) compared with 42% of adults in all occupations. Similar proportions reported smoking a pack or more per day. Blair et al (1985) examined smoking habits by occupations based on a study conducted in the 1950s (Dorn, 1959). They noted welders among the occupations with a higher proportion of cigarette smokers (49%) than that in the entire population (38%). Brackbill et al (1988) provided U.S. data for 1978-1980 showing that 45.4% of male welders smoked cigarettes currently compared to 36.9% for the general population. Subsequently, Nelson et al (1994) reported a smoking prevalence of 42.7% among U.S. welders vs 30.1% for U.S. males in general. Finally, in internal comparisons, welders were reported to have similar smoking habits as internal controls in Norway (Danielsen et al, 1993) but to smoke more than internal controls in Germany (Becker et al, 1989).

Summary: The preponderance of evidence suggests an excess prevalence of smoking among welders, especially compared to the general population. However, as noted by Axelson (1978), such differences are unlikely to explain more than a 20% increase in lung cancer mortality. The finding of a high OR (5.8) for lung cancer among nonsmoking female welders by Wu-Williams et al (1993), although of borderline statistical significance, is consistent with smoking being unable to explain the findings.

Doll (1984) suggested that relative risks for lung cancer of less than about 1.5 cannot be reliably attributed to occupational exposure unless a clear relationship with intensity of exposure can also be shown. Peto (1986) examined the relationship between a proportional smoking ratio (smoking index) and lung cancer SMRs for the 25 principal occupational groups and for welders in England and Wales, 1970-72. There was a high correlation (r=0.72), and he estimated that "much, and perhaps all, of the lung cancer excess among welders, at least in Britain (an SMR of 151), could be attributable to the effects of smoking, as their smoking was 22% higher than the average." He also noted "Conversely,...that as much as 30% of their lung cancer excess could be occupational in origin", and that "an increase of 30% in the SMR would constitute a substantial hazard; but an occupational risk of this magnitude may be virtually impossible to demonstrate by epidemiological observation unless subgroups with heavier or longer exposure than the majority of welders can be shown to suffer a higher lung cancer risk".

Other carcinogens: Other carcinogens besides asbestos may be present in the welding environment. Ronco et al (1988) suggested their findings support the hypothesis of the carcinogenic properties of welding fume, even if other exposures may also play a role, in this case PAHs, which may be generated when welding is carried out on materials previously treated with mineral oils. The separate contribution of PAHS vs welding fumes to lung cancer risk could not be determined.

To conclude this section on major confounders, let us review one of the most recent studies, that by Jöckel et al (1994), which found a crude OR of 1.35 for lung cancer and welding, in good agreement with results from other studies. However, as the authors point out most of the past studies were not able to adjust for smoking and asbestos. The OR increased with adjustment for smoking (Table 8) but further adjustment for asbestos decreased the estimates. They found no dose-response for welding in general or for oxyacetylene or MMA in particular. The authors commented that the increased risk for mechanics and plumbers in this group (67% in this group had exposure to welding fumes), suggested that the apparent risk in this group is probably not due to exposure to asbestos and /or welding fume alone. "Risk-lowering effect of the confounder adjustment procedure is only seen in those individuals who have been exposed to welding. At the moment this finding cannot be resolved."

6.1.2.5 Summary for lung cancer

The bulk of evidence continues to show, as in 1985, that welders suffer a greater lung cancer incidence and mortality than expected, for example, an increase of 34% overall in the largest study reported by Simonato et al (1991) and somewhat higher or lower in other studies. What can be said regarding the three possible explanations noted in 1985?

Stainless steel as a "hot spot":

In the largest study, by Simonato et al (1991), the greatest "latency" effect (two-fold) between groups with long and short periods of observation, occurred among the predominantly SS welders (those most exposed to Cr), which supported an association of lung cancer mortality with the workplace for this subgroup. The finding of a marked increased risk in the small study reported by Sjogren (1987) is also consistent with a "hot spot" in this group. This explanation is also supported by the evidence that these welders are exposed to hexavalent Cr, that they absorb Cr, that SS welding fume is mutagenic, and that hexavalent Cr increases lung cancer in other settings. However, several pieces of evidence can be found against this hypothesis. First, the association between lung cancer and SS welding in the IARC study was not supported by analyses of estimated cumulative exposure to total fume, Cr, Cr(VI) and Ni. Second, pooling of the findings from the separate SS studies do not show an impressive increase (about 24%). Third, the French study (Moulin et al, 1993) (and that by IARC) failed to show that the risk for lung cancer is higher among SS welders than among MS welders; as Moulin (1995) noted "The differences in level of risk between SS and MS cannot be quantified with precision." This did not appear to support the hypothesis that there are higher risks for SS welders. The evidence for SS as "the" cause of lung cancer is not clear, although the uncertainty may be related in part to limitations of study population size, and future reports may clarify this.

Mild steel welding in general:

The lung cancer risk among MS welders (or welders in general) again has been found to be increased by about 30-40% (34% overall in IARC study; 27% among shipyard welders; 70-80% among nonshipyard welders; 42% by Sjogren and Carstensen, 1986), consistent with many previous studies. However, the large study by Steenland et al (1991) did not find such an excess, although the 95% confidence interval was consistent with a risk as high as 46% increase. The study by Danielsen (1993) provided evidence of dose-response and latency, and is inconsistent with the findings of Steenland; however, Steenland's investigation was based on a much larger number of cases. As was noted in 1985, if the moderate increase seen in some studies of MS welders is real, the cause is not known (i.e. there is no candidate carcinogen and the fume has been shown to be not mutagenic or only weakly mutagenic).

Can it be explained by confounding exposures?

The third possible explanation is that the risk due to welding fume itself is negligible and the confounding effects of smoking and exposure to other specific carcinogens might account for the results. As reviewed above, most but not all evidence available suggests that welders may smoke somewhat more than the general population and other working groups, and that most cohorts of welders have been exposed directly or indirectly to asbestos. The authors of the IARC study (Simonato et al, 1991) noted that the excess observed falls into the range "albeit at the upper limit, which could be explained by confounding effect of tobacco smoke, and the excess from bladder cancer is consistent with this". The excess is unlikely to be explained in total by different smoking habits between the study population and referent population. They also noted that asbestos exposure, with 5 mesotheliomas documented, may have contributed to the excess lung cancer. Whether the excess could therefore be explained by the interaction between asbestos and smoking (which is supra-additive or multiplicative) should be borne in mind.

Conclusion: The recent evidence does not allow one to reach conclusions much different from those 10 years ago. There is some evidence for and against the increases being due to each of the possibilities: other confounding exposures (smoking and asbestos), a contribution due to welding in general, and/ or perhaps SS welding as a hot spot. A final possibility is that the increases are due to chance since the confidence intervals include the null value in many studies. NIOSH (1988) reviewed the health effects of welding, and concluded that "welders generally have a 40 percent increase in relative risk of developing lung cancer as a result of their work experiences. The basis of this excess risk is difficult to determine given uncertainties about smoking habits, possible interactions among the various components of welding emissions, and possible exposures to other carcinogens, particularly asbestos." Consistent with this, in a recent review Sferlazza and Beckett (1991) concluded that welding fume should be included in the category of occupational exposures that are possible or suspected respiratory carcinogens.

IARC (1990) concluded that there is inadequate evidence for the carcinogenicity of welding fumes and gases in animals and limited evidence in humans. The agency considered that welding fumes are possibly carcinogenic to humans (Group 2B), which means "a positive association was found for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence". The review presented above of the evidence for both exposure to asbestos and somewhat greater smoking prevalence among welders than the comparison populations appears to support the presence of confounding factors. Thus, the IARC classification appears appropriate.

It is reasonable that any future studies need to take asbestos exposure into account. In order to clarify this important issue, it is recommended that rather than initiating new cohort studies, it may be more informative to undertake case-control studies within the existing cohorts, in order to examine simultaneously the association of lung cancer with welding, including more detailed MS vs SS exposure data, controlling for (or with individual data on) smoking and asbestos (and other occupational carcinogens). Since preparation of the initial version of this report in November 1995, one such study has been published. Lauritsen and Hansen (1996) conducted a nested case-referent study within a cohort of Danish SS and MS welders. Some of their findings are tabulated below (the adjusted ORs were adjusted for smoking only):

The relative risks tended to decrease with adjustment for smoking; moreover, the risks tended to increase with years exposed up to 15 years only (for MS welding), and up to 5-10 years only (for SS welding), which weakened a causal interpretation. The authors planned to repeat this approach after further follow-up.

6.2 Nonrespiratory Cancers

1985 Report: There were five studies noted, addressing bladder cancer (two studies), and kidney, laryngeal and nasal/sinonasal (one study each).

Recent findings: Table 9 summarizes findings from studies published since 1985 for other cancer sites, Part A is a tabulation of case-control studies, and Part B, findings from the cohort studies. There were marginally increased risks (not significant) for bladder cancer from 2 case-control studies. In the IARC study, there was almost a doubling of risk (which was statistically significant); Simonato et al (1991) noted that this was not related to time since first exposure, nor to duration of employment.

For lymphoma, there were inconsistent findings for Hodgkin's Disease and non-Hodgkin's lymphoma in two case-control studies, both from Sweden, with increases in one study and not in the other. Lymphosarcoma risk for welders was increased in the IARC study (SMR of 171, based on only 6 observed cases). Both cancers represent types that have not been reported frequently before. According to Simonato (1991) "These sites do not appear to be related to time since first exposure, nor to duration of employment."

There was a weak association for kidney cancer in one case-control study, and in the census study by Sjogren and Carstensen (1986). The multicentre study by IARC also found a small nonsignificant excess (SMR 139, 12 cases) but there did not appear to be any relation with exposure. There was an increase in prostate cancer mortality in the IARC study and in one of the cohort studies by Tola (1988), concentrated among shipyard and MS welders, that was not related to exposure. Cancer incidence for prostate cancer was significantly increased in the IARC study (SIR 146, 95% CI 102-202, 36 cases). Leukemia represents a new finding in the case-control studies, suggestive of a higher risk for myeloid leukemia in one study and chronic myeloid leukemia in another.

Further work will be required to confirm these associations of nonrespiratory cancer and welding, including demonstration of a relation with time since first exposure or with duration of employment.

7.0 CONCLUSION

In the welding environment, there is potential for exposure to a number of substances. Although the individual toxicities of many of these substances have been fairly well documented in nonwelding settings, data on the effects of multiple chemical exposures are generally lacking. Welders may suffer both acute and chronic health effects associated with welding fume and gases, including confirmation of outcomes previously observed in 1985, as well as some new findings. In general, however, it is not possible to relate health effects to specific contaminants or welding processes.

With respect to acute effects, acute (mostly respiratory) events continue to be observed, mostly as case reports. These include upper respiratory irritation, acute pulmonary intoxication (which can be fatal), metal fume fever, and pneumonia (for which at least one group has concluded that "there are strong grounds for the classification of lobar pneumonia as an occupational disease in welders"). Compared to the findings in 1985, there is now evidence for acute (short-term) changes in pulmonary function among welders, that appears to be associated with higher exposures or absence of ventilation systems. The incidence of asthma was found to be slightly increased among welders in one prospective study (Wang et al, 1994) with no difference in MS versus SS welders; suspected occupational asthma was also reported more frequently among welders in the UK SWORD scheme than among the working population in general (Meredith et al, 1991).

With respect to chronic health effects, the available epidemiologic studies of respiratory effects remain mostly cross-sectional in design, although several longitudinal studies have now been reported (as was recommended in 1985). Some but not all of the studies continue to demonstrate an increased prevalence of symptoms (including chronic bronchitis as well as other symptoms) among welders compared to referents. While non-smokers were affected in some studies, there was some evidence for an interaction with smoking, with greater effects seen among smokers. The longitudinal studies also demonstrated more frequent development of some respiratory symptoms among welders than controls, although not chronic bronchitis. Similarly, there is evidence from some studies for enhanced deterioration of pulmonary function among welders compared to referents, affecting the small airways more frequently than the large airways, and with greater effects observed among smokers in some studies (interaction). However, these changes of chronic lung disease were not seen consistently. Only one study (Groth, 1989) found dose-response relationships for pulmonary symptoms, and only Cotes et al (1989) provided evidence that an exposure index contributed to changes in pulmonary function. There have been several recent case reports of pulmonary fibrosis among welders in the absence of silica exposure but there remain no studies of the incidence of fibrosis among welders. An epidemiologic investigation among symptomatic welders with radiological abnormalities suggested that the fibrosis does not seem to depend on the presence of silicosis.

With respect to nonrespiratory chronic effects, an increased prevalence of neuropsychiatric symptoms has been reported among welders, but confirmation with objective neuropsychological tests is required. It is possible that any effects, if they exist, may be due to metals which are seen in other occupational (nonwelding) settings. Most of the new studies of renal function provide little evidence for renal function abnormalities among welders. In one recent report by Nuyts et al (1995), an increased risk of chronic renal failure was found for exposure to welding fumes, but no dose-response relationship was demonstrated. Some but not most studies of semen quality found a deterioration among welders. However, the studies suffer from weaknesses in methodology including low response rate and possible recall bias; in addition, there were inconsistencies between studies of MS vs SS welders. There is limited evidence that the risk of Wilms' tumour is increased among the offspring of welders.

The recent studies of mutagenicity (in vitro) continue to show that SS fume (particularly MMA/SS) is mutagenic, and the activity correlated with the hexavalent chromium content while MS (and MIG/SS) demonstrated much less activity. New findings that were not found in 1985 are provided by the cytogenicity studies conducted in lymphocytes of welders. Although these studies continue to show no increases in sister chromatid exchanges among welders, several studies have demonstrated genotoxic effects on lymphocytes of MMA/SS welders, involving chromosomal aberrations and DNA-protein cross-linking. However, the implication of these markers of genotoxicity for disease is uncertain at present.

Most of the studies reported during 1985 or after, consistent with those reported previously, continue to document a moderate (i.e. 30-40% increase) in lung cancer risk among welders. However, the findings are not consistent. While the large European multicentre study conducted by IARC (Simonato et al, 1991) showed an overall increase in lung cancer mortality of 34%, a moderately large, well-conducted study of U.S. nonshipyard MS welders by Steenland (1991) found no excess, with no dose-response, and RRs less than 1 on internal comparison to nonwelders. This study was rated highest in quality and was probably the one with the least potential for exposure of subjects to asbestos. The studies of SS welders have been limited by small sample size, and other than one study from Sweden by Sjogren et al (1987), have not shown increases in lung cancer mortality that are greater than those among MS welders in the same cohorts. Future studies of SS welders may be more informative. The two main confounders to consider among welders are asbestos exposure and smoking. There is evidence from many studies that welders are exposed to asbestos based on finding mesotheliomas in these cohorts (especially at shipyards), and that welders tend to smoke more than the general population. IARC (1990) concluded that there is inadequate evidence for the carcinogenicity of welding fumes and gases in animals and limited evidence in humans, and classified this as possibly carcinogenic to humans (Group 2B), which means "a positive association was found for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence". Given the evidence for confounding exposures, this would appear to be the case. For example, in a recent case-control study by Jöckel et al (1994), the OR for lung cancer among welders was reduced (to about 1.2) when adjusted for asbestos. In order to clarify this issue, case-control studies within the existing cohort studies should be undertaken, to examine simultaneously the association of lung cancer with welding, including detailed exposure on MS vs SS, while controlling for smoking and asbestos.

Taken as a whole, there continues to be evidence that prolonged exposure to welding fumes and gases that existed under past and perhaps current conditions may be associated with both acute and chronic health problems in welders. Several of these associations represent outcomes for which evidence had not been present in 1985. Because welders compose important proportions of the workforce and may suffer inordinately from certain relatively common conditions (such as pneumonia, non-malignant respiratory disease, and possibly lung cancer and other diseases) as well as conditions specific to welding such as MFF and acute cross-shift pulmonary reactions, this should be considered an important public health problem.

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APPENDIX 1
EXECUTIVE SUMMARY OF 1985 DOCUMENT¹

The numerous welding and cutting processes, the variety of base metals and types of consumables (e.g. welding rods) combine to form a complex array of many different exposure environments. Fusion welding, in which metals are joined by heat, includes gas and electric arc processes; the latter is the most common welding technique and has received the most study for health effects. It has been estimated (Stern 1983a) that two major arc welding technologies [shielded metal welding (SMAW) with stick electrodes; and gas metal arc welding (GMAW) with continuous wire] applied to mild steel, stainless steel or aluminum, account for combinations practised by 70 per cent of welders. The Hatch Report (1985) suggested that these estimates are also applicable to the Ontario situation. The welding process produces potential respiratory hazards inherent in the welding process itself, including a particulate fraction, which is largely respirable metal oxide fume, and gases, of which ozone and oxides of nitrogen are most dangerous. The welding environment may also contain contaminants that are, strictly speaking, extraneous to the welding process, such as gases (for example, phosgene formed from decomposition of chlorinated hydrocarbons remaining on metal surfaces after degreasing), and particulates such as those resulting from surface paint or from bystander exposure to asbestos or silica.

Certain welding techniques used on particular metals may produce process-specific hazardous exposures: for example during SMAW, and to a lesser extent, GMAW, of stainless steel, exposure to hexavalent chromium may occur; during GMAW with aluminum or stainless steel excessive ozone exposure may occur. Also high exposure to nitrogen dioxide may occur in confined spaces and potentially toxic exposures can be associated with welding with specific consumables or on specific coatings. As a generalization, (but with those few exceptions just described), exposures to constituents do not generally exceed individual threshold limit values or similar criteria, if total fume is kept to about 5 mg/m³ (Stern, 1981a).

Studies have shown that urinary (and blood levels of chromium and nickel are increased in stainless steel welders, as are the urinary aluminum concentrations of aluminum welders. Pathological investigations, and more recently, magnetopneumography, have demonstrated that pulmonary dust burdens in welders are increased relative to non-welders. The latter technique has been used to estimate the amount of lung-retained metal contaminants; average clearance for mild steel dust was estimated to be 20 per cent per year (Kalliomaki et al., 1983d).

Investigations in rats indicate that there may be differences in pulmonary clearance between fume types; for example, chromium from GMA/stainless steel fume was cleared slowly (half-time 240 days) but was clearly rapidly from SMA/stainless steel fume (half-time 40 days).

Acute welding-associated health effects in humans consist mainly of case reports related to the upper and lower respiratory tract system. Such intoxications have resulted in acute pneumonitis, bronchitis and pulmonary edema including fatalities associated with exposure to ozone, oxides of nitrogen, phosgene and cadmium fume. These exposures are largely process-dependent as described above, occur in confined spaces, or are due to a lack of awareness of the composition of consumables or coatings. At lower concentrations, eye and throat irritation may be due to, for example, ozone or fluorides. There have been reports of occupational asthma with stainless steel welders, probably due to chromium or nickel. Metal fume fever (MFF) is an acute febrile illness of short duration that affects up to 30 per cent of welders and results from inhalation of freshly formed metal oxides, most commonly that of zinc. The cause is not known but the syndrome resolves leaving no apparent chronic disorder. Although MFF occurs below the threshold of 15 mg/m³ proposed by Drinker et al., (1927), data are insufficient to confirm the occurrence of attacks below 5 mg/m³. Also, in comparison with their wives, welders have been found to suffer from excess mortality due to pneumonia. It is possible that some deaths were due to acute exposures that were not recognized as such.

Because of the multitude of processes, confounding exposures (e.g. cigarette smoking) extraneous to the welding process itself, poor study design and lack of environmental data, the existence and magnitude of the burden of chronic disease in welders have not been easy to determine. Thus, the focus has continued to be on the respiratory tract. Welders do appear to exhibit more absenteeism attributed to respiratory (especially lower respiratory) tract disease compared to non-welders (McMillan, 1981; Fawer et al., 1982). These epidemiologic studies which assess chronic respiratory effects in welders are all cross-sectional in design) and thus suffer from the problems inherent in this study design); most of these studies are concerned with mild steel welders. Nevertheless, there appears to be a consistent increased prevalence, compared to the comparison groups employed, of chronic pulmonary symptoms (particularly sputum production and cough) in both smokers and non-smokers, and in both shipyard and non-shipyard welders. However, there is not sufficient data with which to relate this finding to duration of exposure, to a specific constituent within welding fume or to a particular level of such a constituent. There is a suggestion, also determined from cross-sectional studies, of a difference in lung function between welders and available controls, indicating an excess in welders of mild obstructive airways disease. Longitudinal prospective studies will be necessary to determine the incidence of such abnormalities and to clarify the rate of decline with time.

Siderosis, a pneumoconiosis due to pulmonary deposition of iron particles, appears as nodular radioopacities on chest X-ray. Siderosis itself is considered to be benign, without fibrosis, and if fibrosis is present, is considered to be due to exposure to other dusts, such as crystalline silica (Parkes, 1982). The prevalence of siderosis has been shown to increase with duration of exposure (Attfield and Ross, 1978). However, no studies have been reported which would permit a correlation between exposure level to iron oxide and the development of X-ray changes. Despite the apparently benign nature of siderosis, there are a number of case reports of symptomatic pulmonary disease accompanied by fibrosis and emphysema; these cases are documented by lung biopsy or autopsy (Stern et al. 1983). Morgan and Kerr (1963) attributed these effects to mixed dust exposure while Stern et al. (1983) have suggested that the fibrogenic potential of welding fume may involve exposure to hexavalent chromium or NO₂. Investigations of other chromium-exposed working populations, however, provide little evidence to suggest a role for chromium in the production of chronic non-malignant respiratory disease. Although NO₂ is an experimental fibrogen, Parkes (1982) considered that there was no adequate proof that intermittent exposure to NO₂ causes emphysema in humans. Moreover, as there is no estimate of the incidence of fibrosis in welders (only case reports), it is not possible to demonstrate that an excess incidence in welders does, in fact, exist.

Traditionally, the search for effects associated with exposure to welding fume and gases has focused on chronic respiratory disease, while non-respiratory effects have been neglected (Zielhuis and Wanders, 1985). Consequently, the reason for the apparent lack of association of welding with non-respiratory effects may be due to a lack of appropriate investigations. Chronic Neurologic disorders attributed to manganese exposure have been rarely described. Contact dermatitis with patch test results demonstrating a sensitivity to chromates has been reported in welders, but it could not be demonstrated that the welding exposure was responsible for the sensitization.

Stainless steel, but not mild steel, welding fume appears to be mutagenic in in vitro tests in bacteria and in cultured mammalian cells. The mutagenic effects appeared to be associated with the water soluble fraction and hexavalent chromium has been considered as one of the agents responsible for this activity. The only two studies reported have failed to detect chromosomal changes in lymphocytes of stainless steel welders, but these studies did not exclude the possibility of point mutations.

The welding environment contains a number of known or suspected metal carcinogens, two of which, nickel and chromium, appear in significant concentrations in stainless and some alloy steels. In addition, pyrolytic decomposition products from paints used on mild steel contain a mixture of organic materials of unknown carcinogenicity, and bystander exposure to carcinogens, such as asbestos, may occur.

Although some studies (mostly case-control studies) have suggested welders have an increased risk of some non-respiratory cancers, further work is needed to confirm these findings.

Attention has been drawn to assessing the possible risk of lung cancer in welders because of the presence in welding fume of metals of known or suspected carcinogenicity in other settings, the respirable nature of the fume, and the route of entry by inhalation. There is, however, no experimental evidence documenting the carcinogenicity of welding fume. Studies based on death certificates and/or census returns, on shipyard welders, and on non-shipyard welders are consistent with a relative risk for lung cancer of the order of 1.3 or 1.4 compared with referent groups, usually national mortality rates (Peto, 1985). Investigations in England and Wales (Registrar General, 1978) but not in Sweden (Sjogren, 1980) have suggested that welders may smoke somewhat more than the general male population. This increased lung cancer risk may be due to the confounding effects of smoking (and perhaps exposure to other occupational carcinogens). Alternatively, mild steel welding may involve little or no risk, but certain processes, in particular stainless steel, may constitute a "hot spot" (Stern 1983a,b) with a higher risk of lung cancer. This explanation considers that stainless steel welding fume contains hexavalent chromium, that stainless steel welders absorb chromium, that stainless steel welding fume contain mutagenic compounds, that chromium (VI) appears to be the (an) active contributor to this mutagenicity, and that there are recognized increased relative risks for lung cancer in other industries where workers are exposed to chromates. The only published evidence of an increased lung cancer risk in stainless steel welders is the study by Sjogren (1980) in which a 4-fold relative risk was reported, but this study was very small (based on only three cases) and needs to be confirmed. Any risk from nickel appears negligible compared to that from chromium (VI) (Stern, 1983a).

The third possible explanation for a slightly increased risk of lung cancer in welders is that long-term employment as a welder of any type may cause an increase in lung cancer after a sufficient latency period has elapsed (for example, 20 years), as demonstrated by Beaumont and Weiss (1981). This was one of the only studies to include an analysis of findings by duration of exposure and latency. No relationship with duration of exposure was found in this study. There is, as yet, no candidate carcinogen identified in mild steel fume, and mild steel fume has not been shown to be mutagenic.

The available epidemiologic studies of lung cancer in welders generally suffer from methodologic limitations (small population size, confounding exposures, mixed processes, absence of quantification of exposure data, absence of analysis by duration of exposure or by latency). To decide whether the association between lung cancer and welding is a causal one, large cohorts of welders consisting of groups with long exposure to stainless steel and mild steel who have been followed for more than 20 years from their first exposure to welding, must be assembled. The existing studies do not meet these criteria.

Taken as a whole, there is reason for concern that prolonged exposure to excessive concentrations of welding fume under past and possibly present conditions may present some degree of hazard to the health of welders. But the data do not permit the health effects to be related to cumulative duration of exposure, much less to levels of specific constituents which can be deemed safe or not safe, as they relate specifically to the welding environment.

APPENDIX 2
Criteria Used to Assess Validity of Studies of Non-Malignant Respiratory Disease (Symptoms, PFTs)^a

APPENDIX 3
Criteria Used to Assess Validity of Cohort Studies of Lung Cancer in Welders^*

TABLE 1: Characteristics of Studies of Chronic Respiratory Morbidity in Welders, 1985 or after
Study	Mur	Sjogren	Zober	Kilburn	Lyngenbo	Groth
Country (Year)	France (1985)	Sweden (1985)	Germany (1985)	US (1989)	Denmark (1989)	Denmark (1989)
Design	Cross-sectional	Cross-sectional	Cross-sectional	Cross-sectional	Cross-sectional	Cross-sectional
Study Subjects	346 arc welders from factory producing industrial vehicles; participation not stated	64 Al (100% participation); 46 SS welders (all participated); 149 railroad (RR) welders (none refused)	All welders with 8 or more years experience, aged 23-63 employed in 12 metal working companies; 305 (>90%) participated: MMA and GMA welders on MS and SS	226 Midwestern non-shipyard welders without asbestosis with > 15 yr welding	74 high-exposed welders from cohort of welders completing questionnaire (86% responded) who met inclusion criteria: 1)welding >10 hr/wk for > 5 yrs; 2) never smokers; 3) never exposed to "noxious" irritants to airways	2660 welders >34 years of age, from welders and shipbuilding clubs at 9 of country's largest shipyards. Response rate 86% of eligible welders. Of these, 2660 (87%) were active welders or working with welding. 80% were at shipyards.
Control Subjects	214 workers from same factory; random sample of rest of workforce (indirectly exposed); maintenance workers, electricians, mechanics, drivers	Age matched referents for Al and SS welders: • nonwelding industrial workers from same company or geographically nearest company; if possible matched for smoking habits • for RR welders, 70 nonwelding RR workers from same geographical area, not matched for age or smoking	100 workers of similar age and smoking habits drawn from various industrial complexes (participation not stated)	370 Michigan men previously studied; some had exposure to welding and asbestos	Recruited from 2 cohorts of metal workers (shipyard and other metal companies) and 203 (56%) of 356 workers from installation companies completing questionnaire who 1) never welded; and met 2) and 3) as for welders. 38 electricians met criteria; included 23 for age matching	881 electricians working primarily in same geographical areas in Copenhagen and Odense. Response rate 64% of 1376 electricians selected.
Exclusions	Painters excluded from control group, as were managers and clerks	RR welders in remote part of country	None stated except those < 8 yr exposure	217 welders who had worked in shipyards, 36 welding < 5 yr; 65 men with signs of asbestosis on CXR	Smokers excluded. 1 participant who took asthma medication before lung function test	< 34 years of age
Outcome	Standardized resp sx questionnaire; CO uptake test; single breath N2 washout test, breath holding CO lung diffusion test, spirometry before and after acetylcholine	Symptoms from modified BMRC questionnaire; pulmonary function; calibrated spirometers	Modified EC resp sx questionnaire; clinical exam; lung function; CXR	Modified ATS questionnaire, CXR, pulmonary function at least 16 hr after work; calibrated spirometer	Pulmonary function (lab's own normal values used as reference), diffusing capacity, N washout volume.	Questionnaire based on BMRC and ATS used (self-administered)
Blinding of assessors	Not stated	Not stated	Not stated	Not stated	Not stated	Not stated
Exposure	Classified by metal welded (Al, MS, SS), process (sem- automatic vs manual), closed vs open workplaces, MS 70-80%, total dust 6.4mg/m3, Al 3mg/m3; automatic & semi-auto now >90%; replaced manual welding over previous 10 yrs; no specific ventilation devices except for welding inside tanks; never exposed to asbestos	Range of exposures: TIG-Al 90%ile < 5 mg/m3 MIG-Al 50%ile > 5 mg/m3 Coated electrodes SS 50%ile 5 mg/m3, 90%ille 10 mg./m3 TIG-SS 90%ile 5 mg/m3 Coated electrodes overlay rails: 75%ile 5 mg/m3, 90%ile 10 mg/m3 Coated electrodes in rail splicing 50%ile 5 mg/m3, 90%ile approx 18 mg/m3	BZ concentrations: - during welding with coated electrodes 3.3- 270 mg/m3 (> MAK of 8mg/m3 in 93%); -during welding with electrode wires 4.2-317 mg/m3 (>8mg/m3 in 63%); -TIG: none exceeded MAK; -Exceeded Ni in 5%, Zn 10%, Pb 15%, Cu 30%, Fe oxide 30%, Total Cr 60% for SS	Not measured	Predominantly MMA-MS	90% worked with MMA welding with coated electrodes. 76% welded > 10 years (average 17 years). 50% welded > 10 years. "High exposure" defined as welding for 10 hr/wk for 5 years. Low exposure was remaining welders.
Confound- ers measured	Age, smoking, ht, wt, length of exposure	For SS & Al: age, smoking, geog area; For RR: geog area only	Age, smoking	Age, smoking, ht	Age, smoking, ht	Age, smoking habits, years welded, working with metal grinding, flame cutting, and exposure to vapours from paints and varnishes
Analysis (calculated by GML)	x2, t-test, no multivariate control for smoking, separate results for NS (OR)	x2, t-test MH test for stratification; separate NS results presented	%, no multivariate analysis (OR; MH OR adj for age)	Multiple linear regression	Linear regression (age, ht included); (OR)	x2, logistic regression
Conclusion	Similar prevalence of respiratory sx and radiologic abn; slight increase in bronchial hyper-reactivity; minor impairment in lung diffusing capacity; sx and PF worse in manual welders and welders in closed spaces; smoking seemed to interact with welding CO lung transfer more impaired in smoking welders than smoking controls. Effect of welding was negligible in NS and light smokers	All welders reported higher frequency of chronic bronchitis (after smoking) but smoking stronger determinant than welding; all welders had significantly more resp sx than referents; symptoms higher in Al welders (O3) and SS welders (Cr); resp sx not related to total particles; PF not affected in any of groups	No difference in sx for age < 43; increased chronic bronchitis in NS welders > 43 but not significant;; PF: No remarkable increase in pulmonary disease; higher prevalence of non- severe restrictive changes in older NS welders not connected with higher prevalence of irregular shadows on CXR	Symptoms not compared to referents; Long-term exposure to welding fumes and gases reduced flows in small airways of welders without asbestosis; decreased flows in NS welders; Interaction: that there was greater decrements in current smokers than NS suggests that welding exposure and smoking interact	Significant reduction in lung function (mostly obstructive) in welders	Welders had significantly increased prevalence of upper respiratory sx for all age and smoking groups, and increased prevalence of dyspnea. Welders had significantly increased prevalence of chronic bronchitis than controls with dose-response relation, in all smoking groups, and relation with years welded.
Abbreviations: Sx=symptoms; MS=mild steel; Al=aluminum; SS=stainless steel; CXR=chest x-ray; NS=non-smokers; CV=closing volume; C/B=caulker/burner; VTG=volume of trapped gas; CO = carbon monoxide

Source: Chinn (1995). Cross-Sectional: Logistic regression analysis of respiratory symptoms in terms of trade and smoking: in (A) smoking is expressed as a categorical variable (yes or no), and in (B) as a continuous variable (g/day)

Symptom	(A) Smokers and non-smokers (n=555)
	Odds ratio (95% CI)                                        (B) Smokers                                                              (n=261)
	Prevalence     %	Smoking	Trade	Smoking x trade	Odds ratio for trade
Cough (C) >3/12 months Phlegm (P) >3/12 months     C+P >3/12 months Wheeze	13.5 16.9 10.3 32.0	1.65 (1.00-7.01) 4.66* (2.72-7.97)     3.02 (1.04-8.78) 3.35* (2.26-4.95)	NS 2.85* (1.57-5.17) NS 2.28* (1.48-3.52)	3.65 (1.57-8.46)     NS 2.95 (1.19-7.26) NS	3.52 (1.49-8.36)
* After allowing for age            Occasional wheeze, 25.9% or regular wheeze 6.1%            Significant when analysis was confined to non-smokers

Longitudinal: Factors associated with development of respiratory symptoms during follow up

TABLE 7:  Summary of Cohort Studies of Lung Cancer in Welders, 1985 or After
Study  (Yr)	MS or SS  (Shipyard?)	Observed/  Expected	SMR or SIR	95% CI	Individual  Control for  Smoking	Comments
Newhouse  (1985)	MS (Yes)	26/ 22.9	113  (191 when compared  with general pop of  Eng & Wales)	80-157	No	1 meso.
Sjogren  (1986)	National census	193/ 136	142	123-163	No	4 meso.
Sjogren  (1987)*	SS (No)	5/ 2.0	249  Internal:      CRR 4.95      Adj RR 7.01	80-581  0.72-34.2  1.32-37.3	No
Tola (1988)*	MS (Yes)  MS (MachineSh)	27/ 23.5  14/ 9.9	115  142	76-167  77-237	No  No	"No excess risk for meso"
Mekild  (1989)*	MS (Yes)	7/ 3.2  Duration:  < 1 yr:   0/0  1-5 yr:  5/0.9  > 5 yr:  1/1.7	221	88-454	No	2 meso in nonwelders.  SIRs in other occup groups
Becker  (1991)*	SS (No)	14/ 12.4	113  Internal:  RR 1.2	67-191  0.6-2.2	Yes	4 meso in welders; none in  turners. SIR with  duration and TSFE.  SIR in turners 109.
Simonato  (1991)	All  MS (Yes)  MS (No)  SS ever  Predom SS	116/ 86.8  36/ 28.6  40/ 22.4  39/ 30.5  20/ 16.3	134  126  178  128  123	110-160  88-174  127-243   91-175   75-190	No	Includes parts ofother  cohorts*  TSFE:<20 yr   20 yr                 210   107                 155   198                 106   152                   80   177  No association with  cumulative exposure
Steenland  (1991)	MS (No)	39/ 36.4	107  Internal:     0.9  By yrs exposure:  2-10           1.13  10-20         0.66  >   20         0.65	76-146  0.60-1.36  0.67-1.90  0.37-1.30  0.29-1.42	No	Very little asbestos (1 meso,  prior job)
Moulin  (1993)	All welders  Controls  MS (Yes)  MS (No)        < 20 yr exp        20 yr exp  Ever SS  Pred SS	19/ 15.3  44/ 46.7  3/ 3.3  9/ 5.7     4/4.1     5/1.5  3/ 3.3  2/ 2.0	124   94   91  160       97     324  92  103  Internal:  1.29	75-194  68-126  19-267  73-302        26-249        105-755  19-269  12-371  Not given	Yes	3 deaths from meso in  shipyard controls.  Internal RR similar to ratio  of SMRs (1.32)
Danielsen  (1993)	MS (Yes)  Shipyard controls  15 yrs latency:  Welders  High exp welders  (> 3 yrs)  Very high exp (5 yrs  exp)  Shipyard controls	9/ 3.6  45/ 33.6  8/ 2.6  6/ 1.6  4/ 1.0  3/ 0.8	250  134  308  375  400  135	114-475  98-179  135-608  138-819  110-1020  96-186	No	4 meso in nonwelders  Internal analysis: see below

TABLE 7:  Summary of Results of Cohort Studies of Lung Cancer in Welders, 1985 or After Internal Analysis of Danielsen et al (1993)
Exposure Group  (compared to other  shipyard production  workers)	Without Lag Time		With Lag Time (10 yrs)
	Emp 5 yrs	Emp > 5 yrs	Emp 5 yrs	Emp > 5 yrs
	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)
Welders  Burners  Office workers	1.7 (0.5-5.5)  2.4 (0.6-9.9)  0.7 (0.3-1.6)	3.0 (1.3-6.9)  2.3 (0.3-16.4)  0.7 (0.3-2.0)	1.8 (0.5-5.7)  2.6 (0.6-10.6)  0.7 (0.3-1.9)	3.2 (1.3-8.1)  2.6 (0.4-19.1)  0.8 (0.3-2.6)

TABLE 8:  Summary of Results of Lung Cancer Case-control Studies in Welders, 1985 or After
Study (Yr) (Country)	Source of Cases and Controls	No. of Exp Cases	Odds Ratio	95% CI	Comment	Adj for smk
Buatti (1985) (Italy)	Cases among residents of Florence admitted to hospital; hospital controls (from medical service)	7	2.8	0.9-8.5		Yes
Kjuus (1986) (Norway)	Cases from 2 hospitals in industrialized areas of Norway	28 16	1.9 3.3	0.9-3.7 1.2-9.3	All welders SS welders	Yes Yes
Lerchen (1987) (US)	Pop-based, identified from New Mexico Tumor Registry; controls through RDD; 65 from Medicare rolls	19 6 13	3.2 2.2 3.8	1.4-7.4 0.5-9.1 1.4-10.7	All welders Shipyard Not shipyard (manuf, const, petroleum & gas transmission, foundries, welding repair shops)	Yes Yes Yes
Shoenberg (1987) (US)	Incident cases from 6 areas of New Jersey (hospitals, path records, cancer registry, DC) (1980-81); controls for interviewed cases were random sample from drivers license file; for deceased cases, controls were from mortality files.	38   Not     stated	1.2 3.5 2.5 3.8	0.8-1.9 1.8-6.6 1.1-5.5 1.8-7.8	Welder or flame-cutter Shipyards Without reported exposure to asbestos Based on supplemental information	Yes Yes Yes Yes
Benhamou  (1988)  (France)	Hospital-based; controls had diseases not related to tobacco	18	1.4	0.8-2.9		Yes
Ronco (1988) (Italy)	Pop-based; in 2 industrial areas of Italy. All males who died of lung cancer. Controls were sample of males dying of other cases	6	2.9	0.9-9.8		Yes
Rinsky (1988) (US)	Nested case-control in cohort at Portsmouth Naval Shipyard	41 236	1.1 1.5	0.8-1.7 1.2-1.8	Probable exposure to welding by-products Probable or potential exposure * Asbestos and radiation exposure also present	No No
Hull (1989) (US)	Pop-based cancer registry in LA County. Cases were welders with pulmonary cancer; controls were all other welders with nonpulmonary malignancy	30 38 34 17 56 61 38 31 37 37	1.1 0.9 0.9 0.6 1.6 1.3 0.6 1.4 1.7 1.8	0.6-2.7 0.5-1.8 0.5-1.8 0.3-1.4 0.8-3.1 0.6-2.3 0.3-1.2 0.7-2.8 0.9-3.1 0.9-3.2	MMA Gas-shielded SS high alloy steel MS MMA on SS Confined space Asbestos exposure Shipyard (no latency) Shipyard (10 yr. latency)	No
Wu-Williams (1993) (China)	Female cases and controls from general pop in Shenyang and Harbin, China	11 5	3.3 5.8	0.9-11.9  P<0.1	All lung cancers Nonsmokers	Yes -
Siemiatycki (1991) (Can)	Population-based; controls were mostly cancers at other sites	36 18	1.6 1.6	1.1-2.4 0.9-2.9	Any exposure (90% CI) Substantial exposure	Yes Yes
Jöckel (1994) (Germany)	Hospital-based study; new cases with histologically confirmed cancer from 1 hospital in Bremen and 2 in Frankfurt, 1988-91; controls were random sample from registries of residents	108 " 104 "	1.35 1.5 1.2 1.6 1.3	-    -    0.8-1.9   -    0.8-2.0	Crude Ever/Never welding Adj for smoking & asbestos Ever oxyacetylene or MMA Adj for smoking & asbestos	No Yes Yes Yes Yes

Endnotes

¹ All references in this Appendix have not been included in the Reference section.

a Adapted from Stock (1991)

^* Adapted in part from ACOHOS (1983)