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Re: Cancer risk from occupational acrylamide exposure

Editor,

Granath and colleagues take issue with our update of a cohort of acrylamide (AMD) workers from three U.S. plants[1] claiming that "it exemplifies the shortcomings of studies of this type to detect moderate influences of specific causative factors on cancer mortality or incidence." To support their contention that we overlooked a small but "unacceptable" increase in cancer risk, they performed a crude quantitative risk assessment. Granath et al. suggested that we perform a within cohort dose-response analysis with all malignant neoplasms as the endpoint as a means of attaining greater statistical power. They further contend that a priori focus on specific cancer sites implicated in previous experimental animal studies is mostly a consequence of the pattern of background incidences in the animal strain used. While choosing a generic health outcome such as all cancer sites combined will certainly increase statistical power, it also greatly reduces the ability to evaluate the all important specificity of an exposure-response relationship. It is unlikely that even the most potent carcinogenic agent will increase the risks of all cancer sites to a level that can be detected with epidemiological methods.

We were fully justified in using cancer site-specific findings as the focus of our epidemiological investigation. The use of cancer site- specific findings from experimental animal studies to formulate a priori testable etiologic hypotheses for human studies is an effective, accepted method commonly employed in occupational epidemiological research. Animal studies can be particularly helpful when investigators are faced with a paucity of extant epidemiological evidence such as in the case of AMD. This practice does not preclude, however, the exploratory investigation of other non-implicated sites as long as the related findings are interpreted in light of their hypothesis generating nature.

We agree that for many of the a priori cancer sites examined in our study, the statistical power to detect a moderate mortality excess (1.5 to twofold or greater) was low, a point addressed in the discussion section of our paper. However, the power of our study to detect a twofold or greater excess in lung cancer, the endpoint of primary concern, at the one -sided 5% significance level was in the excellent range (0.87), as would be the power to detect a similar excess of pancreatic cancer in a future update of this cohort.

Granath et al. overlook a fundamental point - occupational cohort studies of the type we used to evaluate cancer mortality risks among AMD exposed workers are neither designed nor necessarily well suited for quantitative risk assessment purposes. Occupational cohort studies are purposely not designed to detect small excesses in the range of 5-15% deemed by Granath et al. as unacceptable. The primary reason for this is that excesses of this magnitude could easily be due, at least in part, to one or more confounding factors. Observational epidemiological studies usually cannot discriminate among such small mixed effects, and are generally most useful for detecting increases in risk that exceed 50-100% as these are unlikely to be due to uncontrolled confounding. Statistical power considerations notwithstanding, the fact remains that our study is the largest and most comprehensive study of AMD exposure conducted to date, and will continue to provide useful epidemiological Information through future updates and analysis.

Gary M. Marsh
Ada O. Youk
Lorraine J. Lucas
Laura C. Schall

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Re: Cancer risk from occupational acrylamide exposure

Editor,

Recently the results of a comprehensive epidemiological follow up study of cancer mortality in cohorts with occupational exposure to acrylamide was published.[1] With the exception of a weak significance for a raised incidence of pancreas cancer the study arrived by and large at the conclusion that there is "little evidence for a causal relationship between exposure to acrylamide and mortality from any cancer sites". The study updates and confirms an investigation 10 years earlier of the same cohorts.[2] The analysis was based on standardised mortality ratios (SMR) in comparison with US national or relevant county mortality statistics. It exemplifies the shortcomings of epidemiological studies of this kind to detect moderate influences of specific causative factors on cancer mortality or incidence. The investigators praise themselves of having carried out "the most definitive study of the human carcinogenic potential of exposure to acrylamide conducted to date". The results, however, pose questions. Could unacceptable risks be detected? Which risks would have been expected?

For the US workers the average cumulative exposure is given to 0.25 mg/m3 y. (We assume this to correspond to exposure of the whole factory staff to 0.25 mg/m3 for 365 eight-hour working days). At an alveolar ventilation rate of 0.2 L/kg min this exposure would mean a cumulative uptake of about 9 mg acrylamide per kg body weight. This dose corresponds to a lifetime (70 years) uptake of 0.35 µg/kg d. According to the estimate of U.S. EPA[3] this would correspond to a cancer risk of 1.6 10^-3. An estimate based on the multiplicative model[4] would arrive at a ca 3 times higher risk, 5 10^-3. With a cancer mortality in the Western World countries of 0.18, these figures correspond to an 1-3% increase of the cancer mortality risk, i.e. a RR of 1.01-1.03. Since about one fifth of the workers were defined as exposed (with greater than or equal to 10^-3 mg/m3 years) the relative risk in the exposed group due to inhalation of acrylamide may have been about 1.05-1.15.

Although it is doubtful that these risk increments could be considered negligible, they would not be detectable in a study of the present kind. Since uptake via the skin often occurs in work leading to inhalation of acrylamide it is possible that the true risk increments are considerably higher. If we assume the total relative risk (from inhalation plus dermal uptake) to be in the range of 1.1-1.2, it is a pertinent question whether this risk increment is detectable within the large material studied by Marsh et al.[1]

Like many other materials of similar kinds the data are far from ideal for epidemiological analyses. The main reasons for this are the skew distribution of duration of employment, the incompleteness of data for smoking, and the healthy worker effect. The healthy worker effect leads to a deficit in death rates from all causes, in the present study by about 20% for all causes except cancers. Deficits in SMR for all malignant neoplasms and for certain tumour types are also often significant, although with a disturbing influence of a significantly increased SMR for lung cancer in an earlier period. (The significant decrease in lung cancer deaths as well as deaths in diseases of the circulatory system from 1925- 83 to 1984-94 would be compatible with a drastic reduction, before 1984, of smoking.) It is expected that the healthy worker effect comprises cancer, at least to some extent, as well as other causes of death.

A straightforward way of overcoming the healthy worker effect is a within cohort analysis of the regression of mortalities or incidences on the estimated dose. Marsh et al.,[1] have done this for each of a few selected tumour sites. Due to too few observed deaths in each dose interval the statistical power of this material is, however, too small to show anything.

This analysis of individual sites, avoiding a pooling of data that would increase the statistical power, illustrates the widespread dogma that different cancer types are affected specifically by carcinogens. It has been shown for a few mutagenic carcinogens including acrylamide that a linear multiplicative model, P_j = P⁰_j (1+ ß D), can be fitted to experimental cancer incidence data and, for radiation, to human data.[5] P_j and P⁰_j are the total and background risks of tumour at site j, D the dose and ß a relative risk coefficient that is (at least approximately) the same for all tumour sites j. ß is thus applicable to pooled data for groups of sites or for all (responding) sites. Although analysis of death risks associated with specific tumours has its indisputable value, a restriction of significance estimation to individual sites leads as a main effect to a loss of statistical power. For related reasons the identification of certain sites as "interesting", with reference to response to acrylamide in animal experiments, is mostly a consequence of the pattern of background incidences P⁰_j in the animal strain used.

The authors of the paper,[1] possess a material of extreme value in further efforts to clarify the carcinogenic potency of acrylamide. In view of the importance of this question we urge the authors of the paper to continue their work, particularly with analyses of regression on pooled data, primarily for all cancer, with and without exclusion of smoking related sites.

Fredrik Granath
Dept of Medical Epidemiology,
Karolinka Institute

Lars Ehrenberg
Dept of Genetic and Cellular Toxicology,
Stockholm University

Birgit Paulsson
Margareta Törnqvist
Department of Environmental Chemistry,
Stockholm University,
S-106 91 Stockholm,
Sweden

1. Marsh, GM, Lorraine, JL, Youk AO, Schall LC. Environ Med 1999;56:181-190.

2. Collins JJ, Swaen GMH, Marsh GM, Utidjian HMD, Caporossi JC, Lucas LJ. J Occup Med 1989;31:614-617.

3. U.S. EPA, United States Environmental Protection Agency. Assessment of Health Risks from Exposure to Acrylamide. 1990 U.S. Environmental Protection Agency: Washington, DC.

4. Törnqvist M, Bergmark E, Ehrenberg L, Granath F. [Risk Assessment of Acrylamide] (in Swedish) National Chemicals Inspectorate, Solna, Sweden. 1998 PM 7-98.

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Re: Dose-response relationship between acrylamide and pancreatic cancer

Editor,

In their 1999 study of workers exposed to acrylamide, Marsh et al conducted an SMR analysis and fit several relative risk regression models to the data.[1] In each analysis, they found risk of pancreatic cancer elevated by about twofold for workers in the highest cumulative exposure group, but risk of pancreatic cancer did not increase monotonically with cumulative exposure in any of their analyses. Duration of exposure was monotonically related and mean intensity showed a nearly monotonic relationship with pancreatic cancer risk.

The cut points Marsh et al chose for the cumulative exposure groups are based on multiples of current and proposed regulated levels of exposure intensity.[1] [2] Because these cut points resulted in small numbers of expected deaths in the low and intermediate exposure groups, 1.08 and 2.74 respectively, we have regrouped the data to attempt to obtain more stable SMRs. These results are presented in Table 1 and indicate a monotonic dose-response pattern with the SMRs increasing from 0.80 to 1.31 to 2.26.

Table 1. Observed deaths, expected deaths, and SMRs for cancer of the
pancreas, all US workers, 1950-94, local county comparisons, two
lowest exposure groups combined.
 

In part based on the absence of a pattern of monotonically increasing risk with increased cumulative exposure, Marsh et al. argue that, "our findings for cancer of the pancreas should be interpreted with caution, in the context of an exploratory analysis to generate hypotheses."[1] Nevertheless, given the sufficient evidence in experimental animals for the carcinogenicity of acrylamide.[3] this study plays an important role in the evaluation of safety for occupational exposures to acrylamide.

When data are sparse, it is not always clear how best to choose cut points; the grouping we have shown results in a finding that is more compatible with the findings for duration and for intensity of exposure. It would be interesting to see if a regrouping of the exposure categories alters the results of the analyses based on internal comparisons.

MR. Schulz
I Hertz-Picciotto
E van Wijngaarden
J Calderon Hernandez
Department of Epidemiology,
University of North Carolina at Chapel Hill

LM. Ball
Department of Environmental Sciences and Engineering,
University of North Carolina at Chapel Hill

1. Marsh GM, Lucas LJ, Youk AO, et al. Mortality patterns among workers exposed to acrylamide: 1994 follow up. Occup Environ Med 1999;56:181-90.
2. Collins JJ, Swaen GH, Marsh GM, et al. Mortality patterns among workers exposed to acrylamide. J Occup Med 1989;31:614-17.
3. International Agency for Research on Cancer. Acrylamide In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans; Some Industrial Chemicals Volume 60. Lyon, France 1994.