Specialist Medical Review Council
Reasons for Decision
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Assessment of cigarette smoking theory against Bradford Hill criteria
Strength of association
An association between cigarette smoking and prostate cancer has been found in only a few studies, and in each case it has been weak. There are confounders and biases that could account for the positive results, rendering the results of those positive studies of little importance in the overall assessment of causation in epidemiological terms. Thus, this criterion cannot be said to have been met.
Dose response effect
The few studies that have shown a positive relationship have shown inconsistent or weak dose response relationships. However, confounding could account for whatever dose response relationship has been observed. The study that produced the most significant dose response effect, that by Honda (Appendix, item 10(d)), was methodologically flawed : there was selection bias; differential response bias; different methods of data collection; only relatively small numbers were involved; and no control of potential confounders. As a result, this study can be given very little weight.
Therefore, it cannot be said that a dose response effect of any significance has been shown between cigarette smoking and prostate cancer.
Consistency of findings
No association has been found in a substantial number of studies in which cigarette smoking has been considered. It is only in a few studies that positive results have been found. There is thus no sufficient consistency.
Time relationship
All of the studies that showed positive results were consistent with smoking preceding the onset of prostate cancer. Thus, the criterion can be said to have been met in those studies. However, this is the weakest of all the criteria and, without more, cannot be relied upon to show a causal relationship.
Biological plausibility
The only suggestions of biological mechanisms are those concerning cadmium and N-nitrosamines derived from tobacco smoke. However, as set out above, the information is speculative in regard to prostate cancer.
Specificity of the association
As cigarette smoke contains a large number of carcinogens, this criterion is not applicable in the current matter. Therefore, it need not be met.
Coherence of the evidence
Overall, the evidence of an association between smoking and prostate cancer is weak and inconsistent, being largely restricted to one or two studies in North America that, in the investigators' own opinions, are only tentatively findings. The inconsistency of the studies, together with the failure to satisfy other epidemiological criteria, means that there is not a coherent synthesis supporting the proposition.
Conclusion
The epidemiological criteria, not having been satisfied in relation to cigarette smoking and prostate cancer, there is no sound medical-scientific evidence that justifies the inclusion of cigarette smoking as a factor in a Statement of Principles concerning malignant neoplasm of the prostate.
HerbicidesThe information available to the Repatriation Medical Authority directly concerning herbicides included items 1(a), 1(b), 1(d), 12 and 13 set out in the Appendix. Item 11 was also said to support the proposition in an indirect way.
Items 1(a) and (b) were written submissions on behalf of the Repatriation Commission to the Repatriation Medical Authority, discussing the various studies.
Item 1(d) was the MacLennan and Smith report, which examined studies by Alavanja et al (1988), Blair et al (1985), Burmeister et al (1981 and 1983), Morrison et al (1992 and 1993), Breslin et al (1988), and the US report of the Committee to Review the Health Effects on Vietnam Veterans of Exposure to Herbicides (the NAS Report) - a committee appointed by the US National Academy of Sciences. MacLennan and Smith concluded:
The studies reviewed can be grouped into those of farmers and related occupations where some chemical exposure (albeit poorly defined) is assumed to have occurred, and a study of mortality in Vietnam veterans. Neither the first group of studies provides sufficient evidence of statistical association, nor does the study of veterans. Hence prostate cancer should be included in the inadequate/insufficient category. Although studies of Vietnam veterans have not shown an increased risk for prostate cancer, veterans have not yet reached the age where prostate cancer is common, and this outcome should continue to be monitored and kept under review.
Item 13 was the report by Blair et al (1992). They conducted a meta analysis of a number of small studies (some showing positive and others showing negative or no association) concerning the association between farmers and various types of cancer. They reported a meta relative risk of 1.08, with a confidence interval of 1.06 to 1.11. The study did not examine any particular risk factors other than the risk of being a farmer. They stated:
The mortality of farmers is favorable in terms of all causes, all cancers combined, and ischaemic heart disease. The low rates for cancers of the lung, esophagus, and bladder, as well as heart disease, may be explained by the low prevalence of smoking observed globally among farmers. In addition, the physical demands on farmers may account for their low body fat and high levels of physical fitness, which in turn may contribute to lower risks for heart disease and colon cancer. Dietary factors (such as high intake of fresh fruits and vegetables), residence in areas with little air pollution, and selective migration may influence the deficits of cancer observed, but these factors have not been evaluated among farmers.
In contrast to the deficits for most major disease categories, farmers had significantly elevated risks for leukemia, multiple myeloma, Hodgkin's disease, melanoma, and cancers of the lip, prostate and stomach.
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For cancers showing excess risks among farmers, the MRR estimates are not large. It is perhaps not surprising that the relative risks from these summary measures were small because the broad occupational category of farmer was all that was available for these analyses.
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To overcome this bias, future studies of farmers should focus on carcinogenic risks from specific exposures, including pesticides, fertilizers, fuels and engine exhausts, organic and inorganic dusts, solvents, ultraviolet light, and zoonotic viruses. Such studies may provide explanations for the rising incidence of certain cancers and the carcinogenic potential of environmental agents that are much more difficult to evaluate in the general population.
Item 12 was the report by Morrison et al (1993), in which the researchers stated:
This large cohort study suggests that exposure to herbicides results in an increased risk of dying from prostate cancer. There is evidence of an exposure-response relation between herbicide exposure and prostate cancer mortality. Tests for trend were statistically significant. Adjustment for the potentially confounding effects of other farm exposures did not alter the risk relation. No other farm exposure examined was associated with any clear pattern of increased or decreased risk.
The possibility that finding an exposure-response relation between herbicides and prostate cancer reflects some undetected (and hence, uncorrected) bias cannot be discounted. This is made particularly difficult because of the absence of clear risk factors for prostate cancer (except for age and family history). The only other likely possible confounder that was uncontrolled for in this study was diet: there is evidence that a high-fat diet predisposes men to developing prostate cancer, and farmers in this cohort as a group ate a relatively high-fat diet. However, for dietary fat to explain the relation between herbicides and prostate cancer, fat consumption for farmers would have to increase with increasing acres sprayed with herbicides.
Herbicide exposure was inferred from self-reported farm practices from the 1971 Census. However, it is not known who applied the herbicides, but merely how many acres were treated with herbicides. The extent of use of protective equipment when applying herbicides is not known. No information is available regarding actual absorbed doses of herbicides. However, reasonable agreement was found between what was recorded for individual farm operators on various censuses of agriculture with regard to exposure variables such as the number of cattle and acres sprayed with herbicides, suggesting that exposures over time were not badly misclassified.
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To our knowledge, this is the first study to have sufficient power to examine adequately the issue of herbicide exposure and the risk of prostate cancer, as only small studies have been reported previously. Of five studies of manufacturing cohorts that reported an association between phenoxy herbicides and prostate cancer, four were weakly positive. Two studies of pesticide applicators were weakly negative, while one small study of herbicide applicators was positive.
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There is insufficient evidence from animal studies to determine if phenoxy herbicides are carcinogenic.
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It has been speculated previously that farmers may be at an increased risk of prostate cancer because of exposure to fertilizers, possibly contaminated with cadmium. This is not borne out by our study, which found a slight decrease in risk for farmers who used fertilizers.
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The nature of this study prevents concluding that farm exposures other than herbicides are unrelated to the risk of dying of prostate cancer. The main limitation of the study, nondifferential exposure misclassification, is likely to have biased any positive or negative farm exposure toward the null. This may mean that other risk factors due to farm exposure were not detected because of exposure misclassification coupled with relatively low risks. However, restricting the analysis to subgroups of farmers less likely to be misclassified did not strengthen the exposure-response relation for any exposure other than herbicides, suggesting that other exposures were not likely to be related to prostate cancer risk. Even given the limitations of this study, it is superior to previous studies both in size and information on farm and sociodemographic variables available on individual farmers.
Study findings of an association between herbicides and prostate cancer should be considered tentative because of the relatively low increases in risk and because an association has not been noted previously. However, the cohort design obviates recall bias concerns. The positive association between herbicides and prostate cancer is not likely to have resulted from the types of biases to which a study of this nature is vulnerable.
It is relevant to note that in the single epidemiological study that examined this topic with any rigour, the only statistically significant relative risk of greater than 1 was for those cases where more than 250 acres were sprayed in a year.
Item 11 was a study by Thune and Lund suggesting that physical activity was negatively correlated with prostate cancer (ie, it produced a protective effect). Dr Horsley submitted that, if that were the case, then one should expect less prostate cancer among farmers than in the average population, thus suggesting that even a small increase in the expected number of prostate cancers above the expected in a herbicide study relating to farmers was more significant than would otherwise be the case in a non-farmer population.
From the above, it can be seen that the evidence of an association between herbicides and prostate cancer is scanty indeed. The researchers acknowledge significant problems with accepting the results of their studies. They acknowledge that there have been very few studies conducted in relation to the issue and that they are inconsistent. The Morrison study appears to be the only one of any substance that has shown a positive association, and then only for the highest level of exposure by farmers.
Strength of association
A weak association has been found in the Morrison study in high exposure cases. The study acknowledges problems with possible confounding factors, and stated that it "should be considered tentative because of the relatively low increases in risk and because an association has not been noted previously".
In light of these difficulties and the weakness of the association, there cannot be said to be sufficient strength of association in relation to herbicides and prostate cancer to satisfy this criterion.
Dose response effect
The Morrison study found a statistically significant dose response . Nevertheless, it is only one study and cannot be given much weight, and on its own, does not meet this criterion.
Consistency of findings
The Morrison study notes that it is the first study of sufficient size to be of any relevance. It mentions a few previous smaller studies, some that show positive associations and others that do not. As a result, there is insufficient information on which to find that this study is consistent with other studies dealing with the same suggested association.
Time relationship
The Morrison study results were consistent with herbicide exposure preceding the onset of prostate cancer. Thus, the criterion can be said to have been met in that one study.
Biological plausibility
It is said in the submissions that there is evidence that phenoxy-herbicides are animal carcinogens, and they have been associated with other forms of cancer in humans (but not prostate cancer). Furthermore, there was no information before the Repatriation Medical Authority indicating a mechanism by which human prostate cancer might arise from these chemicals, thus there cannot be said to be information before the Council indicating a biological mechanism .
Specificity of the association
Given that herbicides have been said to have been associated with a number of different types of cancer, this criterion may not be particularly relevant or applicable in this matter.
Coherence of the evidence
The Blair meta-analysis indicates that "something associated with farmers" slightly increases their risk of dying from prostate cancer.
The Thune and Lund study merely indicates that physical activity might be protective for prostate cancer. But this does not add to the coherence of the evidence for the proposition that herbicides might cause prostate cancer. It is an unassociated piece of information concerning prostate cancer. It might add to the information suggested in the Blair study that something associated with farmers seems to be associated with a slightly greater risk of prostate cancer in that group, but it cannot be said to particularly add to the coherence of the suggested herbicide association.
Additionally, the acknowledged failure to account for possible confounding in these studies . makes it difficult to achieve a coherent synthesis supporting the proposition.
Conclusion
The Council is of the view that there was insufficient information available to the Repatriation Medical Authority for it to have included in the Statements of Principles a factor relating to herbicides. This view is supported by the conclusion of MacLennan and Smith. However, the Council is also of the view that the matter is worthy of future consideration and should be kept under review by the Repatriation Medical Authority should further information come to light on the subject.
Inability to obtain appropriate clinical management
The Repatriation Medical Authority included, as a factor that can contribute materially or aggravate malignant neoplasm of the prostate, the inability to obtain appropriate clinical management.
There was no written information before the Repatriation Medical Authority relating to that issue, but the Council can well understand why it was considered necessary to include that factor in the Statements of Principles.
As a matter of logic, if the Defence service authorities are under a duty to provide medical treatment for service personnel, and fail to do so, then if, as a result of that failure, the course of the disease progresses faster than it would have progressed had appropriate clinical management been provided, then, it must be said that the disease has been made worse by service, and the Commonwealth would be liable to pay pension.
In relation to prostate cancer, it is well known that the appropriate clinical management can, in fact, be to do nothing, but, clearly, there may well be cases where the cancer is active and it would be negligent not to take positive action to arrest its growth. The failure to do so in such circumstances should give rise to liability.
Therefore, while there was no written information available to the Repatriation Medical Authority on that issue, applying their expertise, experience, and common sense in relation to the issue, would mean that the information could be regarded as sound medical-scientific evidence, on the basis of subparagraph (a)(ii) of the definition of sound medical-scientific evidence in subsection 5AB(2), which states, "in accordance with generally accepted medical practice, would serve as the basis for the diagnosis and management of a medical condition".
Other factors
During the course of the Council's review suggestions of other causal factors have arisen, including a high-fat diet, age, and genetic predisposition. However, most of the information before the Repatriation Medical Authority related to the smoking and herbicide questions. In any event, it is difficult to see how age or genetic disposition can be related to service. The material available to the Authority that related to high-fat diet and other lifestyle factors was not considered to be of sufficient quality to constitute sound medical-scientific evidence.
Given that there is very little information on these matters that can be taken into account, there is no sound medical-scientific evidence, within the meaning of that term under the Act, on which the Repatriation Medical Authority or the Council could have acted to include any of these other factors in a Statement of Principles.
Conclusion
In relation to the Repatriation Medical Authority Statement of Principles, Instrument No. 95 of 1995 concerning malignant neoplasm of the prostate and death from malignant neoplasm of the prostate, made under subsection 196B(2) of the Act, the Council declares, under subsection 196W(5) of the Act, that:
(a) the Council is of the view that there is insufficient sound medical-scientific evidence to justify the making of that Statement of Principles to include, as a factor, "being exposed to herbicides in Vietnam"; and
(b) the Council recommends that the Repatriation Medical Authority reconsider the inclusion of "being exposed to herbicides in Vietnam" as a factor having regard to the Reasons for Decisions of the Council, the information that was available to the Repatriation Medical Authority when it made that Statement of Principles, together with any further information that may arise from any further studies that might be undertaken following the recommendation in the MacLennan and Smith Report relating to malignant neoplasm of the prostate; and
(c) the Council is of the view that there is no sound medical-scientific evidence that justifies any other amendment of that Statement of Principles.
In relation to the Repatriation Medical Authority Statement of Principles, Instrument No. 96 of 1995 concerning malignant neoplasm of the prostate and death from malignant neoplasm of the prostate, made under subsection 196B(3) of the Act, the Council declares, under subsection 196W(5) of the Act, that the Council is of the view that there is no sound medical-scientific evidence that justifies an amendment of that Statement of Principles.