Veterans and Agent Orange Update 1998 (1999) / Chapter Skim
Currently Skimming:
8 Latency and Cancer Risk
8 Latency and Cancer Risk
Pages 407-433
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 407... ...
presents a methodology to address the four questions listed above concerning the timing of herbicide exposure and the risk of cancer; (2) reviews the literature on herbicide exposure and cancers classified in the sufficient and limited/suggestive categories for results describing how the relative risks vary with time since exposure began or ended; 407
|
From page 408... ...
To adequately study the effects of protracted exposure, detailed exposure histories for each study subject, including the dates at which the individual was exposed and, ideally, the level of exposure, are needed. Appropriate statistical methods have been developed for investigating the effects of exposure accrued as a function of time since exposure (Thomas, 1983, 1988; Breslow and Day, 1987)
|
From page 409... ...
· One person begins exposure to the agent in 1970; a second starts in 1975. They are the same age at first exposure and exposure continues until 1985.
|
From page 410... ...
For this reason, a study of prostate cancer mortality would be less likely to detect the effect of a carcinogenic agent than would a study of prostate cancer incidence, unless the agent increased the severity of disease. On the other hand, since prostate cancer is so common and occurs with an increasing frequency as men age, any study of prostate cancer incidence should examine whether those exposed to the agent of interest develop the cancer at an earlier age than those not exposed.
|
From page 411... ...
In the investigation of latency, changes in relative risks with time since exposure will occur later for mortality studies than for incidence studies, by an amount of time approximately equal to the average time from occurrence of the cancer to death. If the agent has no effect on the probability of death or the age at death from the cancer, then mortality studies will result in a pattern of relative risks "shifted to the right" of the pattern that would have been observed in the corresponding incidence studies.
|
From page 412... ...
For protracted exposures, it is customary to examine the relative risks by time since first exposure, because the earliest detectable increase in relative risk may be a manifestation of the earliest exposure. In fact, relative risks for specific times since first exposure are often the only measures of latency reported for studies of protracted exposure to herbicides.
|
From page 413... ...
In other words, the degree to which an increased risk is statistically detectable depends on the size of the particular data set, as well as the magnitude of both the background level of risk (which in turn depends on the age of distribution of study subjects) and the relative increase in risk (which in turn depends on the exposure level received, variation in susceptibilities, length of follow-up in the study, and true distribution of latency periods among the exposed population)
|
From page 414... ...
How Does the Effect of Exposure Vary with the Age at Which It Was Received? Measures of Interest Relative risks for exposure beginning at various ages are the critical measures needed to address this question.
|
From page 415... ...
Does the Exposure Appear to Act at an Early or a Late Stage of the Carcinogenic Process? Measures of Interest The key statistical measures needed to address this question are the relative risks by age at exposure, the time since exposure began, and the time since exposure ended or, alternatively, the parameters in one of several models of carcinogenesis.
|
From page 416... ...
These are soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, respiratory cancer, and multiple myeloma. Although VAO, Update 1996, and Chapter 7 of this report review the entire relevant literature on herbicide exposure, this chapter discusses only those articles that provide results the committee believes reflect, with reasonable accuracy, the timing of herbicide exposure, and that studied a sufficient number of cases to make some judgment about the patterns of relative risks reported.
|
From page 417... ...
However, even for these cancers, the reports of some potentially informative studies did not include latency results, which suggests a potential for publication bias, although one cannot always know whether researchers did an analysis and failed to report it because the results were uninteresting or simply did not conduct the analyses. Also, both prostate and respiratory cancers are in the "limited/suggestive" evidence category, indicating the committee's belief that the evidence for association between herbicide exposure and these cancers is not conclusive.
|
From page 418... ...
Analyses of lung cancer indicate that the relative risks begin to rise substantially after about 20 years from the initiation of cigarette smoking. Among ax-smokers, the relative risk declines to about 50 percent of that of smokers by 12 years after cessation but then remains fairly constant (and elevated relative to those who never smoked)
|
From page 419... ...
Multiple myeloma (females only) Australian All cancers Vietnam veterans Lung cancer All neoplasms (140-208)
|
From page 420... ...
The pattern of relative risks after reaching the peak and the pattern with age at exposure vary greatly across the agents, probably reflecting different mechanisms of action. Review of the Scientific Literature Since respiratory cancer is fairly common, the committee has focused on studies with at least 10 cases.
|
From page 421... ...
o o .s lo o o TO Ed ~o ~ ~ 8 l ~ o ·C o ~ C VO o o ~ ~ gig En Cq o V, ~o ~ o o Do o ~ ~ .
|
From page 422... ...
These data show that there is no clear pattern according to time since first exposure, but there is also no overall association with respiratory cancer, probably because the exposures were on average only four weeks' duration. In a report on four occupational cohorts involved in phenoxy herbicide and chlorophenol manufacturing in Germany, with 47 lung cancer deaths and an overall SMR of 1.4, Becher et al.
|
From page 423... ...
These results can be found in Table 8-6. TABLE 8-5 IARC International Study of Workers Exposed to TCDD or Higher Chlorinated Dioxins: Lung Cancer Observed and Expected Deaths and SMRs for Men by Time Since First Exposure Time Since First Exposure Observed Expected SMR 0-9 years 34 27.9 1.2 10-19 years 64 61.5 1.0 >20 years 127 110.4 1.2 SOURCE: Kogevinas et al., 1997, Table 5.
|
From page 424... ...
However, based on the review of the evidence in VAO, Update 1996, and Chapter 7 of this report, respiratory cancer is in the "limited/suggestive" evidence category, indicating that the committee believes the evidence for association between herbicide exposure and these cancers is not conclusive. A1though an investigation of latency effects could result in a change in the categorization of evidence, in this case it did not.
|
From page 425... ...
Given the scant data, the committee cannot determine how long it takes before the relative risks return to one. The lack of conclusive data on timing parallels the lack of definitive data on whether exposures to TCDD and other herbicides are causally associated with respiratory cancer.
|
From page 426... ...
If a low rate of immigration is assumed, the calendar-period relative risks will approximate TABLE 8-7 NIOSH Production Workers Study: Prostate Cancer Observed and Expected Numbers of Deaths and SMRs by Time Since First Exposure to TCDD Time Since First Exposure Observed Expected SMR <20 years 6 5.0 1.20 220 years 11 8.9 1.23 SOURCE: Derived from Fingerhut et al., 1991, Table 2.
|
From page 427... ...
In zones B and R there is a decrease in the relative risk with calendar period, although the small number of cases and the fact that this is a mortality rather than an incidence study preclude strong statements about the actual pattern of relative risks.
|
From page 428... ...
suggest that the relative risk for prostate cancer mortality is higher in the early period after exposure begins and declines 11-15 years after exposure. As for respiratory cancer, the extrapolation of latency across studies is very uncertain, since it can vary according to the exposure level and other factors such as age at exposure.
|
From page 429... ...
TABLE 8-9 German Phenoxy Herbicide and Chlorophenol Manufacturing Workers Study: Non-Hodgkin's Lymphoma Observed and Expected Deaths and SMRs for Men by Time Since First Exposure Time Since First Exposure Observed Expected SMR <10 years 0 0.4 0 10 to <20 years 2 0.6 3.6 >20 years 4 0.9 4~3 SOURCE: Becher et al., 1996, Table 4. TABLE 8-10 IARC International Study of Workers Exposed to TCDD or Higher Chlorinated Dioxins: Non-Hodgkin's Lymphoma Observed and Expected Deaths and SMRs for Men by Time Since First Exposure Time Since First Exposure Observed Expected SMR 0-9 years 2 3.2 0.6 11-19 years 8 5.5 1.5 >20 years 14 8.6 1.6 SOURCE: Kogevinas et al., 1997, Table 5.
|
From page 430... ...
that latency can vary not only among individuals, but also according to other aspects of the exposure scenario, such as the magnitude of exposure. Thus, if high exposures in an occupational setting result in a certain pattern of relative risks with time since first
|
From page 431... ...
The evidence suggests that if respiratory cancer does result from exposures to the herbicides used in Vietnam, the greatest relative risk for lung cancer may be in the first decade after exposure, but until further follow-up has been carried out for some of the cohorts, it will not be possible to put an upper limit on the length of time these herbicides could exert their effect. For prostate cancer, the published data are largely uninformative, and conclusions must await more definitive studies, preferably using incidence rather than mortality.
|
From page 432... ...
1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.
|
From page 433... ...
1994. Radon and Lung Cancer Risk: A Joint Analysis of 11 Underground Miners Studies.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.