Veterans and Agent Orange Update 2004 (2005) / Chapter Skim
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6 Cancer
6 Cancer
Pages 201-353
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From page 201... ...
. In this chapter, the Veterans and Agent Orange: Update 2004 committee summarizes and reaches conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds of interest (2,4-dichlorophenoxyacetic acid [2,4-D]
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From page 202... ...
In this chapter, background information about each cancer, including data on its incidence in the general US population, is followed by a summary of the findings described in the previous Agent Orange reports (Veterans and Agent Orange, hereafter referred to as VAO [IOM, 1994] ; Veterans and Agent Orange: Update 1996, hereafter, Update 1996 [IOM, 1996]
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From page 203... ...
Collectively, gastrointestinal tract tumors are expected to account for 19% of new diagnoses and 24% of cancer deaths in 2004. Colorectal cancer is the third most common form of cancer in men and in women, excluding basal- and squamous-cell skin cancers.
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From page 204... ...
. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the compounds of interest and gastrointestinal tumors.
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From page 205... ...
Swaen et al., 2004 Dutch licenced herbicide applicators- mortality 3 0.4 (0.11.3) b Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers- cancer of the digestive organs -- mortality 16 0.7 (0.41.2)
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From page 206... ...
20.7 ± 5.0 vs in females 20.7 ± 5.8 (p = 0.92) Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia 45.3 in Age-adjusted incidence (100,000)
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From page 207... ...
Zone R females 25 1.0 (0.61.5) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents Zones A, B males 7 0.9 (0.41.8)
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From page 208... ...
Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 88 1.1 (0.91.5) Marine Vietnam veterans 17 0.8 (0.41.6)
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From page 209... ...
0.0 in in females Chapaevsk; 1.4 in Samara Regionb VIETNAM VETERANS Studies Reviewed in Update 1998 Crane et al. 1997a Australian military Vietnam veterans Esophagus 23 1.2 (0.71.8)
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From page 210... ...
Collins et al., 1993 Monsanto 2,4-D production workers 3 0.5 (0.11.3) Studies Reviewed in VAO Swaen et al., 1992 Dutch herbicide applicators 4 2.6 (0.76.5)
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From page 211... ...
ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia 22.7 in Age-adjusted incidence (100,000) Chapaevsk; in males 21.7 in Samara regiond Age-adjusted incidence (100,000)
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From page 212... ...
VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000b Air Force Ranch Hand veterans 7 1.5 (0.45.5) AIHW, 1999b Australian Vietnam veterans -- male 188 221 expected (191251)
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From page 213... ...
-- Information denoted by a dash in the original study. ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans' Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture.
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From page 214... ...
Ramlow et al., 1996 Pentachlorophenol production workers 0-year latency 0 - 15-year latency 0 -Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states -- white males 367 1.0 (0.91.1) Bueno de Mesquita et al., 1993 Phenoxy herbicide workers 0 0 (0.04.3)
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From page 215... ...
Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents -- 10-year follow-up -- morbidity Zone B males 3 1.4 (0.44.4) Zone B females 2 1.3 (0.35.4)
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From page 216... ...
VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000d Air Force Ranch Hand veterans 7 1.5 (0.45.5) AIHW, 1999d Australian Vietnam veterans -- male 188 221 expected (191251)
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From page 217... ...
Studies Reviewed in Update 2000 Ojajärvi et al., 2000 Meta-analysis of 161 populations 1.0 (0.81.3) Steenland et al., 1999 US chemical production workers 16 1.0 (0.61.6)
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From page 218... ...
Bertazzi et al., 1989b Seveso residents -- 10-year follow-up Zone B males 2 1.1 (0.34.5) VIETNAM VETERANS Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 38 1.4 (1.01.9)
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From page 219... ...
Studies Reviewed in VAO Thomas et al., 1991 Female US Vietnam veterans 5 2.7 (0.96.2) Breslin et al., 1988 Army Vietnam veterans 82 0.9 (0.61.2)
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From page 220... ...
Index cases were Operation Ranch Hand veterans who sprayed dioxin-contaminated herbicides in Vietnam. Comparison subjects served in Southeast Asia during the same period but did not spray herbicides.
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From page 221... ...
The average annual incidence of hepatobiliary cancers is shown in Table 6-7. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D,
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From page 222... ...
Synthesis The evidence from epidemiologic studies is inadequate to link the compounds of interest with hepatobiliary cancer; no new published information was found to change this opinion. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the compounds of interest and hepatobiliary cancer.
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From page 223... ...
Ramlow et al., 1996 Pentachlorophenol production workers 0-year latency 0 - 15-year latency 0 -Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 2 0.6 (0.12.2) Blair et al., 1993 US farmers in 23 states 326 1.0 (0.91.1)
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From page 224... ...
Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents Zones A, B males 4 1.5 (0.54.0) Zones A, B females 1 1.2 (0.29.1)
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From page 225... ...
Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 8 0.6 (0.31.2) Crane et al., 1997b Australian national service Vietnam veterans 1 -Studies Reviewed in VAO CDC, 1990 US men born in 19211953 8 1.2 (0.52.7)
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From page 226... ...
The average annual incidences reported in Table 6-9 show that men are at a greater risk than are women for those cancers and that the incidences increase with age, although the small number of cases indicates that care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers.
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From page 227... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding.
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From page 228... ...
(ICD-9 160) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 1 0.5 (0.02.9)
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From page 229... ...
veterans with tours 19661970 4 0.6 (0.21.4) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 9 1.0 (0.42.8)
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From page 230... ...
The committee affirms that there is inadequate or insufficient evidence of an association. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous Veterans and Agent Orange reports, the committee concludes that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and oral, nasal, and pharyngeal cancers.
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From page 231... ...
Established risk factors for laryngeal cancer are tobacco and alcohol use, which are independent risk factors and act as synergistic risk factors. Occupational exposures -- long and intense exposures to wood dust, paint fumes, and to some compounds used in the metalworking, petroleum, plastics, and textile industries -- also could elevate risk (ACS, 2004b)
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From page 232... ...
Coggon et al., 1986 British MCPA production workers 4 2.3 (0.54.5) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Age-adjusted incidence (100,000)
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From page 233... ...
Zone R females 35 1.1 (0.81.5) VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 4 0.6 (0.22.4)
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From page 234... ...
Conclusions Strength of Evidence in Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and laryngeal cancer. Biologic Plausibility No animal studies have identified an increased incidence of laryngeal cancer associated with exposure to the compounds of interest.
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From page 235... ...
(2003) provide an update of cancer mortality among 2,187 male Dow Chemical Company employees who worked in production areas where there was a potential for dioxin exposure.
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From page 236... ...
Ramlow et al., 1996 Pentachlorophenol production workers 18 1.0 (0.61.5) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 37 1.0 (0.71.4)
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From page 237... ...
, 13.7 ± 3.8 vs lung cancer in females 14.3 ± 4.6 (p = 0.11) Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Age-adjusted incidence (100,000)
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From page 238... ...
Studies Reviewed in VAO Bertazzi et al., 1993 Seveso residents -- 10-year follow-up- morbidity Zone A males 2 0.8 (0.23.4) Zone B males 18 1.1 (0.71.8)
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From page 239... ...
) Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 212 1.3 (1.11.5)
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From page 240... ...
(2004) describe cancer incidence and mortality in a prospective cohort study of Operation Ranch Hand veterans who participated in aerial herbicide spraying during the Vietnam War.
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From page 241... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and lung cancer, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 242... ...
of Bone and Joint Cancer in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black Males 0.9 1.0 1.1 1.4 1.5 1.2 1.7 1.9 b Females 0.9 1.1 0.5 1.0 1.1 0.3 0.9 0.9 b aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 243... ...
Collins et al., 1993 Monsanto 2,4-D production workers 2 5.0 (0.618.1) Studies Reviewed in VAO Ronco et al., 1992 Danish male self-employed farm workers 9 0.9 (*
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From page 244... ...
AFHS, 1996 Air Force Ranch Hand veterans 0 Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 27 0.8 (0.41.7) Marine Vietnam veterans 11 1.4 (0.121.5)
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From page 245... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and bone and joint cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
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From page 246... ...
of male chemical production workers who worked in areas in which there was a potential for dioxin exposure. Although not statistically significant, the incidence of STS in that cohort was considerably greater than expected (SMR, 2.4; 95% CI, 0.38.6; 2 cases)
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From page 247... ...
Ott and Zober, 1996 Workers exposed in 1953 accident 0 0.2 expected Ramlow et al., 1996 Pentachlorophenol production workers 0 0.2 expected Studies Reviewed in Update 1996 Kogevinas et al., 1995 IARC cohort 11 (*
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From page 248... ...
0.7 (0.22.0) Studies Reviewed in Update 2002 Costani et al., 2000 Residents near a chemical plant in 20 2.3 (1.33.5)
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From page 249... ...
VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.8 (0.112.8) AIHW, 1999 Australian Vietnam veterans -- male 14 27 expected (1737)
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From page 250... ...
Greenwald et al., 1984 New York State Vietnam veterans 10 0.5 (0.21.3) Studies Reviewed in VAO Watanabe et al., 1991 Marine Vietnam veterans 8 1.1 Bullman et al., 1990 Army veterans serving in I Corps 10 0.9 (0.41.6)
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From page 251... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and STS, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 252... ...
in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black Melanomas of the Skin Males 33.0 38.8 0.8 43.1 49.6 1.6 54.1 63.9 4.3 Females 23.7 28.3 0.5 27.0 32.0 2.7 27.9 33.9 1.3 Other Non-Epithelial Skin Cancers Males 3.3 3.3 4.3 2.7 2.9 1.6 4.2 4.3 4.8 Females 1.8 1.7 3.0 1.8 1.8 2.0 2.5 2.8 1.3 aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 253... ...
a OCCUPATIONAL New Studies Swaen et al., 2004 Dutch licenced herbicide 5 3.6 (1.28.3) applicators -- mortality Studies Reviewed in VAO Fingerhut et al., 1991 NIOSH cohort 4 0.8 (0.22.1)
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From page 254... ...
) VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 325 1.3 (1.11.6)
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From page 255... ...
Wiklund, 1983 Swedish agricultural workers 268 0.8 (0.71.0) b ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone A females 1 6.6 (0.947.7)
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From page 256... ...
Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 145 1.0 (0.91.1) Marine Vietnam veterans 36 0.9 (0.61.5)
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From page 257... ...
West coast 20 0.8 (0.51.2) Studies Reviewed in Update 1996 Lynge, 1993 Danish male production workers 4 4.3 (1.210.9)
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From page 258... ...
CDVA, 1998b Australian Vietnam veterans -- female 7c 3 expected (18) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 21 1.4 (0.72.9)
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From page 259... ...
In the analyses limited to Ranch Hand and comparison Air Force veterans, the associations with melanoma are restricted to the stratum of veterans with no more than 2 years of service in Southeast Asia and to a stratum created by the subset of Ranch Hand veterans who served only in Vietnam and comparison veterans who served elsewhere in Southeast Asia. If those categories somehow capture a confounding factor, the appropriate analysis would combine information from each stratum (more than 2 years of service and 2 years or less)
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From page 260... ...
Adjustments for potentially important confounders, however, were not carried out. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and melanoma.
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From page 261... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that finding.
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From page 262... ...
a OCCUPATIONAL New Studies Swaen et al., 2004 Dutch licensed herbicide appliers Melanoma, squamous cell carcinoma, and unknown skin cancer 5 3.6 (1.28.3) Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers Non-melanoma skin cancer 0 -Studies Reviewed in Update 1998 Hertzman et al., 1997 Sawmill workers 38 1.0 (0.71.2)
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From page 263... ...
a OCCUPATIONAL Studies Reviewed in Update 2002 Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides Foremen 1 16.7 (0.292.7) Studies Reviewed in Update 1998 Zhong and Rafnsson, 1996 Icelandic pesticide users 5 2.8 (0.96.6)
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From page 264... ...
VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans Basal-cell carcinoma 121 1.2 (0.91.6) Squamous-cell carcinoma 20 1.5 (0.82.8)
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From page 265... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and non-melanoma skin cancers, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
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From page 266... ...
The committee, therefore, makes its conclusions based on the studies in women. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and breast cancer.
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From page 267... ...
Studies Reviewed in VAO Ronco et al., 1992 Danish family farm workers 429 0.8 (p < 0.05) Manz et al., 1991 German production workers 9 2.2 (1.04.1)
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From page 268... ...
Studies Reviewed in VAO Bertazzi et al., 1989b Seveso residents -- 10-year follow-up Zone B females 5 0.9 (0.42.1) Zone R females 28 0.6 (0.40.9)
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From page 269... ...
Studies Reviewed in Update 2000 CDVA, 1998b Australian Vietnam veterans -- female 17d 5 expected (211) Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 3 5.5 (1.116.1)
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From page 270... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and breast cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
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From page 271... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding.
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From page 272... ...
Lynge, 1993 Danish female production workers 7 3.2 (1.36.6) Studies Reviewed in VAO Ronco et al., 1992 Danish farmers Self-employed farmers 7 0.5 (*
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From page 273... ...
Studies Reviewed in Update 2000 CDVA, 1998b Australian Vietnam veterans -- female 4c 1 expected (05) Studies Reviewed in Update 1996 Dalager et al., 1995 Women Vietnam veterans 4 2.1 (0.65.4)
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From page 274... ...
Studies Reviewed in Update 2000 CDVA, 1998b Australian Vietnam veterans -- female 1b 0 expected (04) a Given when available.
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From page 275... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and female reproductive cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
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From page 276... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was limited or suggestive evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and prostatic cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding.
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From page 277... ...
Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers -- 7 1.3 (0.52.8) Mortality Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides Foremen -- Incidence 2 4.7 (*
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From page 278... ...
ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Age-adjusted incidence (100,000) of 7.0 in prostate cancer Chapaevsk; 22.0 in Samara regionc Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone B males 8 1.2 (0.62.4)
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From page 279... ...
OR 2.7 (0.98.2) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 26 0.7 (0.41.3)
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From page 280... ...
Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 30 0.9 (0.61.2) Marine Vietnam veterans 5 1.3 (0.210.3)
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From page 281... ...
reports an increased risk of prostate cancer in Ranch Hand men compared with national incidence rates (SIR, 1.46; 95% CI,
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From page 282... ...
. The investigators also compared prostate cancer incidence in Ranch Hands with Air Force veterans who were stationed in Southeast Asia but not in Vietnam; there was no significant increase in prostate cancer (SIR, 1.68 vs SIR, 1.64; p = 0.92)
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From page 283... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and prostate cancer, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 284... ...
Synthesis The evidence from epidemiologic studies is inadequate to link herbicide exposure and testicular carcinoma; no new published information was found to change that determination. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and testicular cancer.
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From page 285... ...
Kogevinas et al., 1997 IARC cohort 7 1.3 (0.52.7) Ramlow et al., 1996 Pentachlorophenol production workers 0 -Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White males 32 0.8 (0.61.2)
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From page 286... ...
CDVA, 1998a Australian Vietnam veterans -- male 151d 110 expected (89131) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans -- incidence 30 1.2 (0.43.3)
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From page 287... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committees responsible for VAO and Update 1996 concluded that there was limited or suggestive evidence of no association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and urinary bladder cancer. Additional information available to the committee responsible for Update 1998 led it to change that conclusion to one of inadequate or insufficient information regarding an association.
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From page 288... ...
Swaen et al., 2004 Dutch licenced herbicide applicators- mortality 2 0.7 (0.12.4) Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers 1 0.5 (0.12.8)
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From page 289... ...
Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone A males 1 1.7 (0.212.0) Zone B males 5 1.1 (0.52.8)
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From page 290... ...
Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 11 3.1 (0.911.0) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 80 0.6 (0.21.3)
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From page 291... ...
Conclusions Strength of Evidence in Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the compounds of interest and urinary bladder cancer. Biologic Plausibility No studies have reported an increased incidence of urinary bladder cancer in TCDD-treated animals.
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From page 292... ...
of Kidney and Renal Pelvis Cancer in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black Males 22.0 22.0 30.3 35.1 35.5 41.8 48.2 48.9 54.9 Females 9.8 9.9 13.6 17.0 17.3 23.3 23.4 23.7 29.4 aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 293... ...
Conclusions Strength of Evidence in Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and renal cancer. Biologic Plausibility No studies have reported increased incidence of renal cancer in TCDDtreated animals.
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From page 294... ...
Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers 2 0.9 (0.13.3) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers 13 1.6 (0.82.7)
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From page 295... ...
VIETNAM VETERANS Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 11 3.1 (0.911.0) Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 22 1.2 (0.81.9)
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From page 296... ...
Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and renal cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk. BRAIN TUMORS Tumors of the brain and central nervous system include tumors of the cranial nerves, cerebral meninges (the outer covering of the brain)
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From page 297... ...
The causes of most cancers of the brain and nervous system are not known. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and brain cancer.
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From page 298... ...
Becher et al., 1996 German chemical production workers- subcohort I 3 2.3 (0.56.8) Ramlow et al., 1996 Pentachlorophenol production workers 0-year latency 1 - 15-year latency 1 -Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 3 1.2 (0.33.6)
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From page 299... ...
ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone B males 1 0.5 (0.13.5) Zone B females 3 2.2 (0.77.0)
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From page 300... ...
Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 -Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 39 1.1 (0.81.5) Crane et al., 1997b Australian national service Vietnam veterans 13 1.4 Dalager and Kang, 1997 Army Chemical Corps veterans 2 1.9b ( -- )
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From page 301... ...
(2004) describe cancer incidence and mortality in a prospective cohort study of Air Force Operation Ranch Hand veterans who sprayed Agent Orange while serving in Southeast Asia.
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From page 302... ...
and a nonsignificant increase in Ranch Hand veterans who served during the time of heaviest use of Agent Orange (SIR, 2.18; 95% CI, 0.804.84)
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From page 303... ...
of Non-Hodgkin's Lymphoma in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black Males 26.2 27.1 26.3 36.6 38.5 31.2 52.2 55.5 35.5 Females 18.1 18.4 17.3 28.1 30.2 20.6 36.1 39.3 28.1 aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 304... ...
Bodner et al., 2003 Dow chemical production workers- mortality -- 1.4 (0.62.7) Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers- mortality 3 1.0 Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides -- incidence 2 2.3 (0.38.5)
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From page 305... ...
Studies Reviewed in VAO Hansen et al., 1992 Danish gardeners -- men and women 8 2.0 (0.93.9) Ronco et al., 1992 Danish farm workers -- self-employed and employees 147 1.0 (*
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From page 306... ...
Studies Reviewed in Update 2002 Hardell et al., 2001 Case control study of NHL -- TEQ >27.8 and EA >80 8 2.8 (0.51.8)
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From page 307... ...
) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone A males 1 3.2 (0.423.0)
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From page 308... ...
Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.2 (0.02.6) AIHW, 1999 Australian Vietnam veterans 62 48 expected (3462)
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From page 309... ...
Wisconsin Vietnam veterans compared with Wisconsin veterans 24 1.1 ( -- ) Holmes et al., 1986 West Virginia Vietnam veterans compared with West Virginia Vietnam era veterans 2 1.1 (*
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From page 310... ...
(2003) provided an update of cancer mortality among 2,187 male Dow Chemical Company employees who worked in production areas where there was a potential for dioxin exposure.
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From page 311... ...
(2004) describe cancer incidence and mortality in a prospective cohort study of Air Force Operation Ranch Hand Vietnam veterans who sprayed Agent Orange during their service in Southeast Asia.
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From page 312... ...
For instance, the main cohorts with TCDD, but not herbicide, exposure do not have increased rates of NHL. The occupational and environmental studies reviewed for this report are supportive of the previous committee's findings.
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From page 313... ...
of Hodgkin's Disease in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black Males 2.8 3.0 2.4 3.0 3.1 3.9 3.4 3.9 b Females 1.8 1.8 2.8 1.9 2.2 0.7 2.3 2.4 1.3 aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 314... ...
Becher et al., 1996 German chemical production workers 0 -Ramlow et al., 1996 Pentachlorophenol production workers 0 -Waterhouse et al., 1996 Residents of Tecumseh, Michigan 2.9 (1.13.4) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 2 1.7 (0.26.0)
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From page 315... ...
d Exposed to chlorophenols 50 4.3 (2.76.9) d ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone B males 2 3.0 (0.712.4)
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From page 316... ...
Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.3 (0.03.2) Studies Reviewed in Update 1998 Watanabe and Kang, 1996 Marine Vietnam veterans 25 1.9 (1.22.7)
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From page 317... ...
Michalek et al., 1990; Wolfe et al., 1990 Air Force Ranch Hand veteran mortality 0 -Breslin et al., 1988 Army Vietnam veterans compared with Vietnam-era Army veterans 92 1.2 (0.71.9) Marine Vietnam veterans compared with Marine Vietnam-era veterans 22 1.3 (0.72.6)
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From page 318... ...
(2004) describe cancer incidence and mortality in a prospective cohort study of Air Force Operation Ranch Hand Vietnam veterans who sprayed Agent Orange during their service in Southeast Asia.
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From page 319... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and HD, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 320... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and MM. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding.
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From page 321... ...
Becher et al., 1996 German chemical production workers -- Plant I 3 5.4 (1.115.9) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide appliers 3 2.6 (0.57.7)
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From page 322... ...
ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone B males 1 0.7 (0.15.0) Zone B females 4 3.7 (1.310.2)
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From page 323... ...
Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 2 0.7 (0.15.0) Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 6 0.6 (0.21.4)
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From page 324... ...
The only other new study published since Update 2002 is an update of cancer incidence in the Ranch Hand veterans and the comparison cohort of Air Force veterans. As in the earlier reports from the Ranch Hand study, the small number of cases did not permit an adequate analysis of MM alone.
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From page 325... ...
A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and multiple myeloma, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 326... ...
of Leukemias in United Statesa 5054 5559 6064 Years of Age Years of Age Years of Age All All All Races White Black Races White Black Races White Black All Leukemias Males 13.3 13.7 12.2 20.5 21.4 16.2 31.0 33.1 19.4 Females 8.3 8.5 6.7 12.6 12.9 11.3 17.2 18.4 12.5 Acute Lymphocytic Leukemia Males 1.0 1.1 0.8 0.7 0.7 0.8 1.2 1.3 b Females 0.7 0.7 0.7 0.9 1.0 0.3 0.7 0.7 b Acute Myeloid Leukemia Males 3.4 3.4 3.5 5.3 5.4 3.6 9.0 9.6 5.4 Females 2.5 2.6 1.2 4.4 4.3 4.0 5.6 5.9 4.3 Chronic Lymphocytic Leukemia Males 5.0 5.3 4.3 9.2 10.2 5.9 12.5 13.6 8.1 Females 2.2 2.3 2.3 4.2 4.5 3.3 6.1 6.8 3.5 Chronic Myeloid Leukemia Males 1.7 1.7 2.7 2.4 2.2 3.2 3.9 3.8 3.8 Females 1.7 1.9 1.2 1.7 1.7 2.0 2.5 2.7 1.7 All Other Leukemiac Males 0.4 0.4 b 0.7 0.6 1.6 1.3 1.3 0.5 Females 0.3 0.2 0.7 0.5 0.5 0.7 1.1 1.1 0.9 a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude agespecific rates, 19972001.
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From page 327... ...
However, two human retroviruses have been linked to human leukemias: HTLV-1 appears to cause adult T-cell leukemia or lymphoma; the data that link HTLV-2 to hairy-cell leukemia are less definitive. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and leukemia.
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From page 328... ...
2.7 (20-yr induction) Thörn et al., 2000 Swedish lumberjack workers exposed to phenoxyacetic herbicides 0 -Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers 10 0.8 (0.41.5)
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From page 329... ...
Blair and White, 1985 Residents of Nebraska -- all cases, all leukemia -- farming 1,084 1.3 Burmeister et al., 1982 Residents in Iowa- CCL in white, male farmers 1.9 (1.23.1) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Mortality standardized to Samara region Males 11 1.5 (0.82.7)
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From page 330... ...
Zone B females 2 1.8 (0.47.3) Studies Reviewed in VAO Bertazzi et al., 1992 Seveso residents -- 10-year follow-up Zones A, B, R males 4 2.1 (0.76.9)
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From page 331... ...
CDVA, 1998b Australian Vietnam veterans -- female 1b 0 expected (04) Studies Reviewed in Update 1998 Dalager and Kang, 1997 Army Chemical Corps veterans 1.0 (0.13.8)
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From page 332... ...
The study group consisted of 1,189 Ranch Hand veterans; 1,776 comparison Air Force veterans were included in the analyses using the SEER data. Because of the small number of site-specific cancers among the veterans, all leukemias were combined with MM and the lymphomas to form the category of lymphopoietic cancers.
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From page 333... ...
Synthesis Two new studies of leukemia are updates that detail additional follow-up for herbicide applicators in the Netherlands (Swaen et al., 2004) and Ranch Hand veterans and the comparison cohort of Air Force veterans (Akhtar et al., 2004)
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From page 334... ...
The epidemiologic studies indicated that farming, especially where there is exposure to the herbicides 2,4-D and 2 4,5-T, is associated with significant risk of CLL mortality. Many more studies support the hypothesis that herbicide expo
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From page 335... ...
Malignant transformation of B-lymphoocyte progenitor cells Is apparent in most cases of CLL and NHL, so it is plausible that these diseases could have a common etiology. The only new study of leukemia in the last two years was an update of cancer incidence among the Ranch Hand veterans compared to a cohort of other Air Force veterans.
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From page 336... ...
Burmeister et al., 1982 Residents of Iowa white male farmers using herbicides 1.9 (1.23.1) ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up- lymphatic leukemia Zone A 0 - Zone B 2 1.1 (0.34.4)
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From page 337... ...
SUMMARY On the basis of the occupational, environmental, and veteran studies reviewed, the committee has reached one of four conclusions about the strength of the evidence regarding an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and each of the kinds of cancer studied. As explained in Chapter 2, the distinctions reflect the committee's judgment that, if an association between exposure and a given outcome is "real," it would be found in a large, well-designed epidemiologic study in which exposure was sufficiently high, well characterized, and appropriately measured.
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From page 338... ...
Typically, at least one high-quality study indicates a positive association; often several studies provide positive results, but the results of other studies are inconsistent. In previous reports, the committees found limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and laryngeal cancer, lung cancer, bronchial (tracheal)
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From page 339... ...
Biologic Plausibility Chapter 3 presents details of the committee's evaluation of recent toxicologic studies relevant to the biologic plausibility of a connection between exposure to the compounds of interest and various forms of cancer. Some of the preceding discussions of cancer outcomes include references to papers relevant to specific types of cancer.
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From page 340... ...
340 VETERANS AND AGENT ORANGE: UPDATE 2004 interactions are involved in TCDD-induced carcinogenesis. Recently, the finding that TCDD immortalizes keratinocytes was suggested to be a possible mechanism by which this chemical causes malignancy.
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From page 341... ...
There is, however, considerable uncertainty regarding the doses or body burden at which carcinogenesis may occur. Increased Risk of Disease Among Vietnam Veterans In response to the Agent Orange Act of 1991, the committee was asked to determine (to the extent that available scientific data permit meaningful determinations)
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From page 342... ...
. AFHS (Air Force Health Study)
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From page 343... ...
1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins [see comments]
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From page 344... ...
1993. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands.
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From page 345... ...
1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans.
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From page 346... ...
1991. Cancer mortality in workers exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin.
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From page 347... ...
1997. Mortality and cancer incidence among sawmill workers exposed to chlorophenate wood preservatives.
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From page 348... ...
1999. Serum dioxin and cancer in veterans of Operation Ranch Hand.
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From page 349... ...
1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins.
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From page 350... ...
1993. Some occupational exposures as risk factors for malignant lymphomas.
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From page 351... ...
1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.
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From page 352... ...
2000. Mortality and cancer incidence among Swedish lumberjacks exposed to phenoxy herbicides.
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From page 353... ...
1983. Swedish agricultural workers: a group with a decreased risk of cancer.
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Key Terms
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