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3 Epidemiologic Studies T o assess the presumptive period for the association between exposure to herbicides in Vietnam and their contaminants (2,4-dichlorophenoxyace- tic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] and its con- taminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], cacodylic acid, and picloram) and increased risk of respiratory cancer, the epidemiology literature must be examined. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994) and its updates (IOM, 1996, 1999, 2001, 2003) review the entire relevant literature on herbicide exposure, but this chapter dis- cusses articles that the committee believes reflect, with reasonable accuracy, the length of time between herbicide or TCDD exposure and occurrence of respira- tory cancer with sufficient respiratory-cancer cases to support some judgment about the patterns of relative risks reported. The committee searched the litera- ture for epidemiologic studies on the presumptive period for exposure to TCDD or the herbicides used in Vietnam and the risk of respiratory cancer. No such studies were found. However, evidence regarding the latent period was found and, because that evidence can provide some information related to the presump- tive period, the results of those studies are reviewed in detail. The chemicals of interest that were sprayed in Vietnam were 2,4-D, 2,4,5-T and its contaminant TCDD, picloram, and cacodylic acid. No data are available that are relevant to the latent or presumptive periods that might exist if there were an association between 2,4,5-T or picloram and respiratory cancer. There are also insufficient data on humans to assess the latent period for cacodylic acid and respiratory cancer. Cacodylic acid is dimethylarsinic acid. In addition to being produced for use as a herbicide, dimethylarsinic acid is formed as a me- tabolite in humans after exposure to inorganic arsenic. Many epidemiologic stud- 40

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EPIDEMIOLOGIC STUDIES 41 ies have been conducted on populations exposed occupationally to inorganic arsenic. Although data indicate that dimethylarsinic acid might be the metabolite that mediates the carcinogenicity of inorganic arsenic, the dose-response and kinetics underlying the carcinogenicity of inorganic arsenic compared to expo- sure to dimethylarsinic acid are not characterized well enough to directly ex- trapolate epidemiologic data from inorganic arsenic exposure to dimethylarsinic acid exposure. Therefore, studies of inorganic arsenic exposure are not reviewed here. Of the chemicals, the most data are available on populations exposed to TCDD or 2,4-D. The relevant epidemiologic studies of those chemicals are de- scribed in this chapter. The pertinent discussion that appeared in Update 1998 is included here for completeness. Because respiratory cancer is fairly common, the committee has focused on studies with at least seven cases. REVIEW OF STUDIES The National Institute for Occupational Safety and Health (NIOSH) study of chemical-production workers gives the most detailed account of timing effects and exposure to TCDD (Fingerhut et al., 1991). Standardized mortality ratios (SMRs) for respiratory cancer (lung, bronchus, and trachea) were 0.8, 1.0, and 1.2 for 09, 1019, and 20+ years, respectively, since first exposure to TCDD, on the basis of a total of 85 cases. SMRs for time since first exposure are further stratified by duration of exposure, as reproduced in Table 3-1. An association between TCDD exposure and respiratory cancer is not observed in years 09 after first exposure. Effects begin to be observed in the second decade after exposure began among those with at least 5 years of exposure, and they have not TABLE 3-1 NIOSH Study: Respiratory-Cancer Relative Mortality, by Time Since First Exposure and Duration of Exposure to TCDDa Duration of Exposure to TCDD (years) Time Since <1 14 514 15+ Overall First Exposure (years) Obs SMR Obs SMR Obs SMR Obs SMR Obs SMR 09 3 0.8 3 1.0 1 0.8 0 0.0 7 0.8 1019 6 0.7 5 0.8 9 1.8 1 1.4 21 1.0 20+ 17 1.0 17 1.3 14 1.5 9 1.6 57 1.2 Total 26 0.9 25 1.1 24 1.5 10 1.5 85 1.1 aData from Fingerhut et al. (1991), Table 4. No confidence intervals were provided, but all p- values were greater than 0.05. ABBREVIATIONS: NIOSH, National Institute for Occupational Safety and Health; Obs, observed; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

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42 VETERANS AND AGENT ORANGE disappeared 20 or more years after first exposure. The latency may be longer for those with shorter exposure. A later assessment of this cohort (Steenland et al., 1999) was based on an additional 6 years of follow-up and a job-exposure matrix that ranked 3,538 workers (69% of the cohort) on relative exposure to TCDD. An analysis using Cox regression models and an assumption of 15-year latency after initial em- ployment found a statistically significant trend between exposure and lung can- cer mortality among the workers, with highest mortality in the top two septiles of exposure (hazard ratios = 2.6 (1.35.0) and 1.6 (0.83.4) for septiles 6 and 7, respectively). Analyses were repeated with different values for latency (5, 10, and 20 years, in addition to 15 years). The authors reported that the model based on 15-year latency provided the best fit with the data for the analysis of all cancers combined. No information was provided on the alternative latency as- sumptions for the analysis of lung cancer alone, and goodness of fit in a limited set of models is not necessarily a reliable means of determining the appropriate latent period, which will vary across individuals. One of the largest industrial accidents involving environmental exposure to TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled reaction during trichlorophenol production. On the basis of soil sampling, three areas were defined about the release point: Zone A, the most heavily contami- nated, from which all residents were evacuated within 20 days; Zone B, an area of less contamination that children and pregnant women in their first trimester were urged to avoid during the daytime; and Zone R, a region with some con- tamination in which consumption of local crops was prohibited. Data from Seveso in Bertazzi et al. (1989a,b) and summarized in Tables 3-2a and 3-2b indicate that lung cancer mortality was not increased among those in the exposed areas during the period from 0 to 5 years after the accident but was increased in years 610 for Zones A and B. In the 15-year follow-up of the Seveso cohort, no additional data are presented on latency for lung cancer (Bertazzi et al., 1997), but given the results from several publications, the committee has calculated the relative risk for years 1115 as 1.0 in all three zones. A report on the 20-year follow-up of the Seveso cohort (Bertazzi et al., 2001) is summarized in Table 3-2c. Data are shown for lung cancer (ICD-9 code 162) mortality in men of Zones A and B combined and for periods since expo- sure that are slightly different from the categories displayed in Table 3-2a. A modest increase in lung cancer mortality is observed for years 59 and 1520, but there is no increase in the first period or in years 1014. No latency analyses are presented for Zone R, and the number of lung-cancer deaths in women (four) is too small for an informative analysis of latency. In an 18-year follow-up of Finnish herbicide appliers, Asp et al. (1994) gave the SMRs for respiratory cancer (lung, bronchus, and trachea) relative to the Finnish male calendar-year- and age-specific rates in such a way that SMRs could be calculated by time since first exposure for 09, 1015, and >15 years.

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EPIDEMIOLOGIC STUDIES 43 TABLE 3-2a Seveso Study: Lung Cancer Mortality Risk Ratios in Men, by Calendar Period Relative Risk Time Since Exposure (years) Zone A Zone B Zone R 05 0.0 1.1 0.7 610 2.0 1.8 0.9 1115a 1.0 1.0 1.0 aRelative risks have been calculated by using data from the two published reports. Data from Bertazzi et al., 1997, Table 3; Bertazzi et al., 1989b, Tables 4, 5, and 7. TABLE 3-2b Seveso Study: Lung Cancer Mortality in Men for 15-year Follow-up Relative 95% Observed Expected Risk Confidence Interval Zone A 4 4.2 1.0 (0.42.6) Zone B 34 27.6 1.2 (0.91.7) Zone R 178 194.4 0.9 (0.81.1) Data from Bertazzi et al., 1997, Table 3. TABLE 3-2c Seveso Study: Lung Cancer Mortality in Men, by Years Since First Exposure Zones A and B Time Since First Relative 95% Exposure (years) Observed Expected Risk Confidence Interval 04 9 8.9 1.0 (0.52.0) 59 15 9.7 1.5 (0.92.6) 1014 14 12.7 1.1 (0.61.9) 1520 19 12.8 1.5 (0.92.4) Data from Bertazzi et al., 2001, Table 7. There is no clear pattern according to time since first exposure, but there also is no overall association with respiratory cancer, probably because the exposures averaged only 4 weeks. Another study from Finland examined the incidence of cancer in a cohort of 152 male workers in a pulp and paper mill (Jappinen and Pukkala, 1991). The cohort was limited to workers employed in 19451961 in jobs with the greatest

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44 VETERANS AND AGENT ORANGE respiratory or skin exposure to chlorinated organic compounds, including TCDD. The expected incidence of cancer was calculated from age- and calendar-specific rates for the mill district. During 34 years of follow-up (19531987), seven cases of lung cancer occurred (standardized incidence ratio, 3.0; 95% confidence inter- val (CI), 1.26.2). Six of the seven cases were diagnosed 15 years or more after initial employment in the mill. The authors acknowledged that company health records showed that six of the cases were in smokers. In a report on four occupational cohorts involved in phenoxy herbicide and chlorophenol manufacturing in Germany, Becher et al. (1996) showed the rela- tive risk to be highest in the first decade (SMR, 1.80) and to decline but remain elevated thereafter (SMR, 1.38 1020 years after exposure, 1.35 thereafter). The chemicals produced included 2,4-D and 2,4,5-T, and exposure to TCDD was also likely in most of the cohorts. Those results are based on 47 lung cancer deaths, and the study had an overall SMR of 1.4. The data are presented in Table 3-3. A different pattern of results was observed in a study of 549 men in the Netherlands employed during 19551985 in a factory whose main product was 2,4,5-T. Bueno de Mesquita et al. (1993) monitored cause-specific mortality for the same 30-year period and identified nine deaths from respiratory cancer (SMR, 1.0; bronchus, lung and trachea). In analyses stratified by time since first expo- sure, six of the respiratory cancer deaths occurred after 20 years of exposure (SMR, 1.7). Hooiveld et al. (1998) extended the follow-up by 6 years (through 1991) and reported SMRs of 1.0 overall (based on 14 deaths) and 1.3 for workers first exposed 20 years ago or earlier. Coggon et al. (1991) examined cancer mortality in the male employees of four British factories that manufactured a variety of phenoxy herbicides. The cohort included 2,239 men who worked during 19631985, and follow-up for mortality was complete through 1987. Nineteen deaths were attributed to respi- ratory cancer (SMR, 1.3; lung, pleua, and mediastinum), but only six of the cases occurred more than 10 years after initial exposure to phenoxy compounds (SMR, 0.9). TABLE 3-3 German Phenoxy Herbicide and Chlorophenol Manufacturing Workers Study: Observed and Expected Lung Cancer Deaths and SMRs for Men, by Time Since First Exposure Time Since First Exposure (years) Observed Expected SMR 95% CI <10 8 4.4 1.8 (0.83.6) 10 to <20 14 10.1 1.4 (0.82.3) 20+ 25 18.4 1.4 (0.92.0) Data from Becher et al., 1996, Table 4.

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EPIDEMIOLOGIC STUDIES 45 TABLE 3-4 IARC International Study of Workers Exposed to TCDD or Higher Chlorinated Dioxins: Observed and Expected Lung Cancer Deaths and SMRs for Men, by Time Since First Exposure Time Since First Exposure (years) Observed Expected SMR 95% CI 09 34 27.9 1.2 (0.91.7) 1019 64 61.5 1.0 (0.81.3) 20 127 110.4 1.2 (1.01.4) Data from Kogevinas et al., 1997, Table 5. The cohorts from Germany, the Netherlands, and England (and the afore- mentioned NIOSH study cohorts) were included in the much larger International Agency for Research on Cancer (IARC) multicohort occupational study (Kogevinas et al., 1997). The IARC study found a weak overall association between exposure to phenoxy herbicides or chlorophenols and lung cancer mor- tality (SMR, 1.1 based on 225 deaths). The SMRs for 09, 1019, and 20+ years in the IARC study were 1.2, 1.0, and 1.2, respectively, on the basis of 34, 64, and 127 lung cancer deaths. The IARC results are shown in Table 3-4. The study of Ranch Hands (Michalek et al., 1998) examines latency for several cancer sites but does not define whether it involves time since first ser- vice, since last service, since start of service in Vietnam, or since last service in Vietnam. This group of veterans experienced fewer respiratory cancer deaths than expected in the first 20 years (3 observed and 5.6 expected) and a slight excess after 20 years (9 observed and 7.2 expected). A report on the Australian veterans who served in Vietnam provides addi- tional information on the time since first year of service (Crane et al., 1997). The first year of service may have been earlier than the first year in Vietnam or the first year of exposure, so latency observed in these data would be longer than the actual latency. The pattern of SMRs for lung cancer deaths during 19801994 (no lung cancers were observed before 1980) was as follows: 2.5, 0.9, 1.3, 1.3, and 1.1 for the periods 25 years, respectively, since the start of service. Note, however, that the SMR of 2.5 in the early period is based on only three lung cancer deaths, whereas the remaining periods had 17, 60, 95, and 35 lung cancer deaths, respectively. The results can be found in Table 3-5. In addition, two recent studies have used toxicokinetic models to obtain a measure of cumulative dose and have used this as an exposure metric in analy- sis of increased cancer risk associated with TCDD exposure. Steenland et al. (2001) estimated cumulative dose from both estimated external exposure and known serum TCDD. The cumulative dose was calculated with a simple one- compartment first-order model, assuming a half-life of 7.1 years. The study

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46 VETERANS AND AGENT ORANGE TABLE 3-5 Australian Vietnam Veterans Study: Observed and Expected Lung Cancer Deaths and SMRs for Men, by Time Since Start of Military Service Time Since Start of Service (years) Observed Expected SMR <10 3 1.2 2.5 1115 17 19.7 0.9 1620 60 45.9 1.3 2125 95 73.0 1.3 >25 35 32.2 1.1 Data from Crane et al., 1997, Table E-19. assumed a background intake of 0.5 pg/kg of body weight per day, leading to a steady-state level of about 5 parts per trillion (ppt) in blood lipids. To estimate risk, the authors assumed an intake of 10 pg/kg per day. The exposure-response analysis used a cumulative TCDD dose and integrated time-specific serum con- centrations over time to obtain a cumulative serum concentration for each per- son in the study. A similar cumulative dose was obtained from exposure scores at the end of exposure, and this did not differ much from the cumulative expo- sure based on serum concentrations. There was an increasing cancer risk with increasing cumulative TCDD dose in the serum, assuming a 15-year lag. The authors acknowledged limitations in their approach, one being the use of a constant estimated half-life; TCDD half-life may vary with body-mass index, initial body burden, and other factors. However, the cumulative dose (derived from serum concentrations) was judged to be a "reasonably good predictor" of cancer risk. The study by Steenland et al. dealt with all cancers, and although the analysis did not deal specifically with respiratory cancer, it does demonstrate a use of cumulative dose measures. Salvan et al. (2001) also used a cumulative dose as an exposure metric to estimate cancer risk, for all cancers and for lung cancer specifically. They exam- ined the NIOSH cohort data by using a minimal physiologic toxicokinetic model that assumes TCDD concentrations to be in dynamic equilibrium among three lipid compartments in the body--blood, liver, and adipose tissue--with assump- tions about TCDD elimination and intake. The model used for analysis of the NIOSH cohort was developed with data on Ranch Hands, for whom serum con- centrations were available at multiple times. The study used three methods to estimate elimination and input, including nonlinear least squares, a nonlinear mixed-effects model, and a hierarchic model with Bayesian analysis. The cumu- lative dose, expressed in ppt-years, was related to the all-cancer risk, assuming a 10-year lag from first exposure. The analysis showed an increase in risk ratio of

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EPIDEMIOLOGIC STUDIES 47 2 for exposures at 100 times background. The authors acknowledged limitations, including an inability to adjust for smoking. Despite the limitations, the value of using a cumulative dose as an exposure metric appears to be upheld. When reviewing those two studies (Salvan et al., 2001; Steenland et al., 2001), however, it must be remembered that the relationships between cumula- tive dose and respiratory-system dose and between dose and response in the respiratory system are not clear. It is assumed that the continuing exposure esti- mated from serum concentrations indicates the degree to which the respiratory system is exposed. Whether the cumulative dose pertains to questions of latency when serum concentration has fallen to the background value is not clear. SUMMARY In reviewing the epidemiologic evidence on the timing of exposure to the chemicals of interest (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and respiratory cancer, the relevant studies had exposure to either the herbicides and TCDD, or TCDD alone. There were no data available on the latent or presumptive period for the individual herbicides. Despite a few suggestions in the literature, based on small numbers of deaths, that the highest risk is shortly after start of exposure, the preponderance of the evidence suggests that risk remains elevated at least 15 and probably more than 20 years after exposure. There is no indication that risks return to background levels during the entire length of follow-up, which in many studies is more than 25 years after exposure ends. Nevertheless, no data have been published at all regarding the time between cessation of exposure to TCDD and risk of respira- tory cancer. The NIOSH study (Fingerhut et al., 1991) does not begin to show an effect until 10 years after exposure, and risks were increased the most 20 years or more after exposure began. Six years later, a follow-up study of this cohort found a statistically significant trend between exposure and lung cancer mortality among workers; a 15-year latency period was the best fit for the study data (Steenland et al., 1999). The data on the Seveso cohort (Bertazzi et al., 1989a,b; 1997) show an increased occurrence of death from lung cancer beginning 610 years after initiation of an exposure. The 20-year follow-up of the Seveso cohort also showed similar elevations in risk for the periods 59 and 1520 years since first exposure (Bertazzi et al, 2001). A study of workers involved in the manufacturing of phenoxy herbicide and chlorophenol showed the relative risk to be high in the first three decades after exposure begins (Becher et al., 1996). A mortality study of a different cohort of male factory workers employed by factories that manu- factured phenoxy herbicides found nineteen deaths attributed to lung cancer (SMR, 1.3); 6 of these cases occurred more than 10 years after exposure in the factory (SMR, 0.9) (Coggon et al., 1991). The IARC cohort (Kogevinas et al., 1997) demonstrates elevations in lung cancer in the first and third decade after

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48 VETERANS AND AGENT ORANGE exposure. Among Australian Vietnam veterans (Crane et al., 1997), risks were elevated 2125 years, but not greater than 25 years, after exposure. The latest report on Ranch Hands (Michalek et al., 1998) shows a reduced risk of lung cancer death in the first 20 years after exposure and a slightly elevated risk after 20 years. A study of Finnish pulp and paper mill workers found 7 cases of lung cancer (3.0; 95% CI, 1.26.2); 6 of the 7 cases were diagnosed 15 years or more after initial employment (Jappanin and Pukkala, 1991). Six out of 9 respiratory cancer deaths in a cohort of factory workers involved in the production of 2,4,5-T occurred after 20 years of exposure (Bueno de Mesquita et al., 1993). A follow- up study of this cohort reported 14 respiratory cancer deaths and SMRs of 1.0 overall (based on 14 deaths); workers first exposed 20 years or more earlier had an SMR of 1.3 (Hooiveld et al., 1998). The committee finds evidence in the literature that the time between expo- sure and the detection of respiratory cancer depends on the duration of exposure; this evidence is in the Fingerhut et al. (1991) study, the only analysis that pre- sented a cross-classification of time since first exposure with duration of expo- sure. With latency depending on the duration of exposure, one would not neces- sarily expect to see the same pattern for time since exposure in all studies. Nor would one expect the pattern of risk over time since exposure to be the same in Vietnam veterans as in those exposed in manufacturing plants or through acci- dental environmental releases of the same chemicals. In summary, numerous studies have examined latency by stratifying on time since first exposure using the simplest approaches described in Chapter 2. Some of the data suggest that an increased risk of respiratory cancer occurs within 10 years of first exposure. No analyses examined the presumptive period for TCDD, that is, the time between termination of exposure and the end of an effect on the incidence of respiratory cancer. Data on latency in epidemiology studies provide a framework for the consideration of a presumptive period, but are not sufficient for drawing quantitative conclusions regarding the length of that period. The relationship between cumulative or peak dose in TCDD carcinogenesis is un- known, and the relative importance of the first or any specific window of expo- sures remains unclear because information from epidemiologic studies has not been sufficient to disentangle them. Although risk factors for cancer can be determined in a population, for any given individual who develops respiratory cancer, the exact exposures that contributed to the pathogenesis of that cancer cannot usually be determined with certainty. Therefore, there is no clear indica- tion of the presumptive period; but in many of the studies, there also is no indication that the risk returns to background values during the entire length of follow-up, often more than 25 years. That is, some increased risk remains for at least 20 or 25 years after exposure began. Most of the studies, however, have not followed the cohort beyond 30 years, leaving no data with which to determine a latent or presumptive period beyond that time frame.

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EPIDEMIOLOGIC STUDIES 49 REFERENCES Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlo- rophenoxy herbicide applicators: an 18-year prospective follow-up. American Journal of Indus- trial Medicine 26:243253. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312321. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316 329. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989b. Ten-year mor- tality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129:11871200. Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: a 15-year mortality study after the "Seveso accident." Epidemiology 8(6):646652. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: a 20-year mortality study. American Journal of Epidemiolo- gy 153(11):10311044. Bueno de Mesquita HB, Doornbos G, van der Kuip DA, Kogevinas M, Winkelmann R. 1993. Occu- pational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Nether- lands. American Journal of Industrial Medicine 23:289300. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48(3):173178. Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997. Mortality of Vietnam veterans: the veteran cohort study. A report of the 1996 retrospective cohort study of Australian Vietnam veterans. Canberra: Department of Veterans' Affairs. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetra- chlorodibenzo-p-dioxin. New England Journal of Medicine 324:212218. Hooiveld M, Heederik DJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG Jr, Bueno de Mesquita HB. 1998. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 147(9):891 901. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. Jappinen P, Pukkala E. 1991. Cancer incidence among pulp and paper workers exposed to organic chlorinated compounds formed during chlorine pulp bleaching. Scandinavian Journal of Work, Environment and Health 17(5):356359. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno de Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):10611075.

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50 VETERANS AND AGENT ORANGE Michalek JE, Ketchum NS, Akhtar FZ. 1998. Postservice mortality of U.S. Air Force veterans occupationally exposed to herbicides in Vietnam: 15-year follow-up. American Journal of Epi- demiology 148(8):786792. Salvan A, Thomaseth K, Bortot P, Sartori N. 2001. Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodiben- zo-p-dioxin, TCDD). The Science of the Total Environment 274(1-3):2135. Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI. 1999. Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the National Cancer Institute 91(9):779786. Steenland K, Deddens J, Piacitelli L. 2001. Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. American Journal of Epidemiology 154:451458.