Dear Editor,

In their study from Massachusetts, USA, on characteristics of work related asthma, Breton CV et al. found that individuals with work related current asthma were 4.8 times as likely to visit the emergency room at least once, and 2.5 times as likely to visit the doctor at least once for worsening asthma compared to individuals with non-work related asthma (1). Work related status of asthma was determined by self-report of ever having been told by a physician that asthma was work related.

The proportion of work-related asthma in this study was 6% which is low compared to a recent statement by the American Thoracic society (2), and so may indicate misclassification. The authors state that the timing of the work related diagnosis is not known. This may introduce bias in the results because physicians often hesitate to ask patients about exposure at work (3). In our experience (4), the question of work- relatedness is usually not addressed until further work is in jeopardy due to the disease. If this is the case also in Massachusetts, asthmatics with doctors diagnosed work related disease may have a more serious disease than those without doctors diagnosed work related disease. In part this may explain why those with work related disease were found to visit emergency rooms and see their doctor for worsening asthma more often.

References

1 Breton CV, Zang Z, Hunt PR, Pechter E, Davis L. Characteristics of work related asthma: resulta from a population based survey. Occup Environ Med 2006;63:411-415.

2 American Thoracic Society. Amerivan Thoracic Society Statement: Occcupationa Contribution to the Burden of Airway Disease. Am J Resir Crit Care Med 2003;167:787-797.

3 Milton DK, Solomon GM,Rosiello RA, Herrick RF. Risk and incidence of asthma attributable to occupational exposure among HMO members. Am J Ind Med 1998;33:1-10.

4 Leira HL, Bratt U, Slåstad S. Notified cases of occupational asthma in Norway: exposure and consequences for health and income. Am J Ind Med 2005;48:359-364.

Dear Editor,

The paper by Laakkonen et al., (1) reported a lower than expected rate of lung cancer in textile workers for men and women. The data in this study, as has been previously reported (2), suggest that a dose- response relationship exists for increasing cotton textile dust and lowered lung cancer rates. I would like to make several comments regarding this excellent report on dust exposure and respiratory cancer.

Numerous studies (3-7) have shown that exposure to organic dust, especially that having endotoxin, results in lower rates of lung cancer. These studies (2,3) have evaluated cotton textile and agricultural workers in regard to beneficial effects. Automobile workers exposed to contaminated machinery oils that contain high levels of endotoxin have also been reported to exhibit lower than expected rates of lung cancer (8). This concept has been termed the occupational hygiene hypothesis (9). When studies are adjusted for the major confounder of lung cancer, smoking, the benefits of exposure remained (3,6,7). Recently, a study (7) of women Chinese textile workers, whom few smoked, reported similar findings of reduced lung cancer. In this population, it was determined that the influence of the small number of smokers was negligible on cancer rates and that this population could be considered non-smokers (10). Historically, the reason given for lower rates in these occupational groups was a lower smoking rate, which was also suggested by Laakkonen. If the current studies of workers exposed to endotoxin-containing dust are analyzed in total, there appears to be a dose-response relationship (2), as indicated in Laakkonen’s study, and the confounder smoking is not responsible for these lower rates. A review of smoking rates indicates that cotton textile workers have a similar or higher rate than controls or the general population (11). Similar smoking rates in textile and control populations was initially shown by Henderson and Enterline (12), where rates of 51.9 and 51.2 percent for textile workers in 1967 and the US population (control) in 1970 were observed, respectively. It should also be noted that the epidemiological studies have been supported by animal investigations (13), which suggest a benefit against tumor metastasis. However, there have been epidemiological investigations that suggest exposure to cotton textile dust result in an increased risk of cancer (e.g. brain tumors) (14).

Recently, studies (10,15-17) of women Chinese textile workers have reported reduced rates of cancer in other organ systems beside the lung (e.g. liver, rectum, stomach and esophageal) . This indicates that the benefits of occupational exposure to endotoxin may not be limited to the respiratory system.

It has also been suggested that other occupational groups (e.g. sewage treatment workers) (18) that are exposed to endotoxin may be having reduced cancer rates from exposure. However, for the most part, few investigations on the beneficial effects of occupational exposure have been conducted. It should be noted, that one study (19) of smelter workers that were exposed to selenium also observed a lower than expected rate of lung cancer. This study along with those of agricultural and textile workers indicate that benefits from exposure may be more common than previously thought.

Based on the study by Laakkonen (1) and others (2), additional investigation on the benefits of occupational exposure is warranted. Few would have suggested years ago that exposure to dust in the occupational environment would have a benefit against cancer. However, evidence for such benefits existing is strong and the historical explanation of smoking being the responsible effect of lowered cancer rates in these occupational groups no longer appears applicable. Thus, benefits of organic dust exposure in reducing cancer should be considered a real effect and warrants intense investigation.

Some have suggested that exposure to endotoxin early in life, and possible in the occupational environment, also provides protection against allergy and/or asthma, which has been commonly called the hygiene hypothesis (20). It can be suggested that the mechanisms associated with the hygiene hypothesis and reduced cancer (occupational hygiene hypothesis) are the same or similar. Both appear to involve toll-like receptors and involvement of cytokines (6,11,20). For cancer, it has been suggested that this mechanisms involves pathways that results in apoptosis of the target cell, which is a cancer cell (6,11,21). There is likely an interrelationship between this anti-cancer activity and inflammation.

There are, however, risks of occupational disease (20) from exposure to endotoxin (22) and organic dust (23) and these risks are suggested to outweigh any benefits associated with reduced cancer rates.

References

1. Laakkonen A, Kyyronen P, Kauppinen T, Pukkala E. (2006). Occupational exposure to eight organic dusts and respiratory cancer. Occupational and Environmental Medicine.

2. Mastrangelo G, Fedeli U, Fadda E, Lange JH. 2002. Epidemiologic evidence of cancer risk in textile industry workers: a review and update. Toxicol Ind Health 18: 171-181.

3. Mastrangelo G, Marzia V, Milan G, Fadda E, Fedeli U, Lange JH (2004) An exposure-dependent reduction of lung cancer in dairy farmers. Indoor and Built Environment 13: 35-44.

4. Lange JH, Mastrangelo G, Fedeli U, Rylander R, Lee E. (2003). Endotoxin exposure and lung cancer mortality by type of farming: is there a hidden dose-response relationship? Annals of Agriculture and Environmental Medicine 10: 229-32.

5. Enterline, P.E., Sykora, J.L., Keleti, G,. Lange, J.H. 1985. Endotoxin, cotton dust and cancer. Lancet 2:934–35.

6. Mastrangelo G, Grange JM, Fadda E, Fedeli U, Buja A, Lange JH. (2005). Lung cancer risk: effect of dairy farming and the consequence of removing that occupational exposure. American Journal of Epidemiology. 161: 1037-1046.

7. Astrakianakis G, Seixas N, Camp J, Ray R, Gao DL, Wernli K, Thomas DB, Checkoway H. (2005) Reduced lung cancer risk associated with cotton dust exposure in women textile workers in Shanghai, China. American Journal of Epidemiology 161:S39 (abstract).

8. Schroeder JC, Tolbert PE, Eisen EA, Monson RR, Hallock MF, Smith TJ, Woskie SR, Hammond SK, Milton DK. (1997). Mortality studies of machinery fluid exposure in the automobile industry IV: a case-control study of lung cancer. Am J Ind Med 31: 525-33.

9. Lange JH, Rylander R, Fedeli U, Mastrangelo G. (2003). Extension of the hygiene hypothesis to the association of occupational endotoxin exposure with lower lung cancer risk. Journal of Allergy and Clinical Immunology 112: 219-20.

10. De Roos AJ, Ray RM, Gao DL, Wernli KJ, Fitzgibbons ED, Ziding F, Astrakianakis G, Thomas DB, Checkoway H. (2005). Colorectal cancer incidence among female textile workers in Shanghai, China: a case-control analysis of occupational exposures. Cancer Causes and Control 16:1177- 1188.

11. Lange JH (2006). Reduced lung cancer in workers exposed to organic dust: epidemiological and experimental evidence. Current Topics in Toxicology. (in press)

12. Henderson V, Enterline PE. (1973). An unusual mortality experience in cotton textile workers. Journal of Occupational Medicine.15:717-719.

13. Lange JH. (1992). Anticancer properties of inhaled cotton dust: a pilot experimental investigation. Journal of Environmental Science and Health (Part A). A27: 505-514.

14. Gold LS, De Roos AJ, Ray RM, Wernli K, Fitzgibbons ED, Gao DL, Astrakianakis G, Feng Z, Thomas D, Checkoway H. (2006). Brain tumors and occupational exposures in a cohort of female textile workers in Shanghai, China. Scand J Work Environ Health. 32:178-84.

15. Chang C-K, Astrakianakis G, Thomas DB, Seixas NS, Ray RM, Gao DL, Wernli KJ, Fitxgibbons ED, Vaughan TL, Checkoway H. Occupational exposures and risks of liver cancer among Shanghai female textile workers – a case- cohort study. International Journal of Epidemiology 2006;35: 361-9.

16. Fitzgibbins ED, Ray RM, Gao DL, LI W, Seixas NS, Camp JE, Astrakianakis G, Feng Z, Thomas DB, Checkoway H. (2006) Occupational risk factors for esophageal cancers among female textile workers in Shanghai, China. 163:717-25.

17. Wernli KJ, Fitzgibbins ED, Ray RM, Gao DL, LI W, Seixas NS, Camp JE, Astrakianakis G, Feng Z, Thomas DB, Checkoway H. (2006) Occupational risk factors for esophageal cancers among female textile workers in Shanghai, China. Am J Epidemiol 163:717-25. 18. Lange JH, Mastrangelo G and Thomulka KW (2003) Will sewage workers with endotoxin-related symptoms have benefit of reduced lung cancer? (Letter), Occupational and Environmental Medicine, 60:142-149.

19. Gerhardsson L, Brune D, Norberg IGF, Webster PO. (1985). Protective effect of selenium on lung cancer in smelter workers. Brit J Ind Med 42:617-26.

21. Lange JH, Mastrangelo G, Fadda E, Priolo G, Montemurro D, Grange JM,. (2005). Elevated lung cancer risk shortly after smoking cessation: is it due to reduction of endotoxin exposure? Medical Hypotheses. 65:534-541.

22. Thorn J, Rylander R. Inflammatory response after inhalation of bacterial endotoxin assessed by induced sputum techniques. Thorax 1998:53:1047-52.

23. Christiani DC, Wang XR. Respiratory effects of long-term exposure to cotton dust. Curr Opin Pulm Med 2003:9:151-5.

The Editor Occupational and Environmental Medicine

14th September, 2012

Cadmium, arsenic and lung cancer: A complete picture?

Were the occupational lung cancers among former employees at the cadmium recovery plant located near Denver, CO, USA due to cadmium exposures, arsenic exposures or both? One of us recently suggested that a "simultaneous analysis of lung cancer risks in relation to both recent and distant cadmium and arsenic exposures" was required, and that researchers should "let the data speak and not design an analysis that assumes in advance which of these variables is important".[1] Although the new paper from Robert Park and co-workers [2] does not appear to respond to these suggestions, we believe their data could assist with authoritative interpretation.

Findings from the only other cohort study to carry out an analysis of occupational lung cancer risks in relation to quantitative estimates of cadmium and arsenic exposures (and exposures to other metals) were consistent with the hypotheses that recent arsenic exposures are more important than distant exposures, and that cadmium exposures are unimportant.[3] In addition indirect evidence that a late stage carcinogen was operating at the Globe plant has already been provided.[4] Analyses of recent exposures in the current study could be illuminating and need to be carried out.

In addition, analyses in which the size of the arsenic effect is not constrained need to be reported. Some of the later stages of processing at the Globe plant would only have had exposures to cadmium because the arsenic had already been removed (e.g. solution, pigment). This contrast provides a cell with cadmium effects only. Therefore, there is the potential for separating the independent effects of arsenic and cadmium, without applying constraints to the modelling.

Reference

1. Sorahan T. Cadmium, arsenic and lung cancer: the bigger picture. Occup Med (Lond) 2010;60:236.

2. Park RM, Stayner LT, Petersen MR, et al. Cadmium and lung cancer mortality accounting for simultaneous arsenic exposure. Occup Environ Med 2012;69:303-9.

3. Jones SR, Atkin P, Holroyd C et al. Lung cancer mortality at a UK tin smelter. Occup Med (Lond) 2007;57:238-45.

4. Sorahan T. Lung cancer morality in arsenic-exposed workers from a cadmium recovery plant. Occup Med (Lond) 2009;59:264-6.

1Institute of Occupational and Environmental Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK;

2Environmental and Occupational Health Sciences, University of Illinois at Chicago, School of Public Health (W) M/C 922, 2121 West Taylor St., Chicago, IL 60612, USA

Conflict of Interest:

None declared

Dear Editor,

The authors conclude that 'there was evidence of a persisting risk among process workers first employed since 1953' in the Clydach, South Wales, refinery. Unfortunately, they were unable to incorporate the confounding influence of such well-known predictors of health as attained education, income level and smoking status. An analysis of their data, stratified finely by smoking status, would yield useful information on the independent effect of exposure. The confounding role of smoking behaviour on inferences concerning nickel exposure can be demonstrated by examining a recently published case-control study by one of the authors of lung cancer risk in Norwegian nickel refinery workers.[1]

Table 1, abridged from a corresponding table in Grimsrud et al. (2002)¹, shows clearly that lung cancer risk increases with amount smoked, reaching a 30-fold higher level for the Norwegian study's heaviest smokers.

Table 2 shows that total nickel exposure risk decreases with increasing smoking level, clearly illustrating the complex interaction of disease, exposure and smoking behaviour. The highest exposure risk appears for the Never/Former smokers. However, for this group, the counts of cases in Table 2 (3,23) are almost the same as the counts (4,22) of the cases in Table 1. The significant odds ratios (ORs) for lung cancer were 3.8 for smoking and 5.0 for exposure. Without adjusting for smoking in this group, it is not possible to assess the separate contribution of either exposure or smoking. However, as will be seen, most of the risk associated with exposure comes from this small subset.

This confounding of smoking and exposure effects is not surprising since there was a higher proportion of non-smokers among the controls in the Never/Former smoker group (93 of 234 controls or 40%) than among the cases (4 of 26 cases or 15%) (Table 1). The Light/Medium smoker group also shows relatively more light smokers among its controls (106 of 253 controls or 42%) than among its cases (49 of 146 cases or 34%). The OR for total nickel exposure in this group rises from 12.3 to 22.1 or 1.8 (Table 2). This estimate can be compared with the smoking OR for this group, which rises from 11.7 in Light smokers to 17.7 in Medium smokers or 1.5 (Table 1). These OR values are also not significantly different. The lung cancer risk in the Light/Medium smokers of the study could be attributed to smoking behaviour. Finally, the odds ratio of 0.9 in the heavy smoking group (Table 2) also provides no evidence of risk associated with nickel exposure.

The complete Norwegian case/control dataset would have been required to duplicate exactly the odds ratios estimated using conditional logistic regression models to analyze lung cancer risk as a function of smoking status and total nickel exposure in Table 7 of Grimsrud et al. (2002). However, a simple logistic analysis (Table 3) closely approximates those ORs and their confidence intervals. This good agreement allows us to use our logistic models to examine the relationships between smoking and exposure in the Norwegian study.

These odds ratios by smoking status lead to a conclusion very different from Grimsrud et al.'s. Significantly elevated lung cancer risks are seen for the Never/Former and Light/Medium smoker groups and, for the reasons discussed above, the attribution of this risk to smoking and/or exposure is unknown. These findings could be due to differences in the smoking histories of cases and controls.

A comparison of two logistic models, each containing additive terms for total nickel exposure (2 levels) and smoking (3 levels) as explanatory factors, but one of which also includes a linear interaction term for exposure and smoking, shows that the interaction term is significant (p=0.016).[3] The significance of the interaction term indicates that an analysis that omits it will yield measures of exposure risk that include interaction effects.

Smoking and exposure are strongly related in the Norwegian study. Its authors used a simple model in which the effects of smoking and exposure on lung cancer risk were presumed additive. Our analysis has shown the exposure/smoking interaction effect is significant. When one factor (smoking) has a large effect relative to that of the factor of interest (nickel exposure), the analysis is more informative if done separately for each level of the influential factor.[4] The failure to include this step in the analysis makes it impossible to assess the risk of nickel exposure. This calculation, which could be simply done with available Norwegian data, would inform our understanding of exposure risk in this and other studies, including the current Clydach study.

D.K. Andrews and J.G. Heller

Authors' affiliations

D.K. Andrews, Dept. of Statistics, University of Toronto

J.G. Heller, James G. Heller Consulting Inc., Toronto, Canada, and Dept. of Public Health Sciences, University of Toronto

Competing interests

Inco Ltd financially supported preparation of this letter by the authors. Falconbridge Ltd financially supported research² by the authors underlying this letter.

References

1 Grimsrud TK, Berge SR, Haldorsen T, et al. Exposure to different forms of nickel and risk of lung cancer. Am J Epidemiol 2002; 156: 1123- 1132.

2 James G. Heller Consulting Inc. Report for Falconbridge Limited on Occupational Exposure Limits for Nickel. Falconbridge Ltd., Toronto, Canada. April 8, 2005. [unpublished]

3 The SAS code yields output for two logistic models with and without an interaction term. The first model without the term has a chi squared likelihood ratio of 99.1857 with 4 degrees of freedom (df). The second with the term has a likelihood ratio of 93.4049 with 3 df. Consequently, the addition of the interaction term accounts for a decrease of (99.1857 - 93.4049) = 5.5808 with 1 df. The probability that a chi- square with 1 df exceeds this value is 0.016202, rounded to 0.016 in the text. Alternatively, SAS code yields a p-value of 0.0211 for the test of significance of the interaction term, based on an asymptotic approximation of normality for the distribution.

4 Cox DR, Planning of Experiments. John Wiley and Sons, New Jersey. April 1992. ISBN: 0-471-57429-5.