National Academies Press: OpenBook

Veterans and Agent Orange: Update 2006 (2007)

Chapter: 6 Cancer

« Previous: 5 Exposure Assessment
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 261
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 262
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 263
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 264
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 265
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 266
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 267
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 268
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 269
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 270
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 271
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 272
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 273
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 274
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 275
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 276
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 277
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 278
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 279
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 280
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 281
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 282
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 283
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 284
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 285
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 286
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 287
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 288
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 289
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 290
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 291
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 292
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 293
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 294
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 295
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 296
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 297
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 298
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 299
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 300
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 301
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 302
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 303
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 304
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 305
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 306
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 307
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 308
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 309
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 310
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 311
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 312
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 313
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 314
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 315
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 316
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 317
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 318
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 319
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 320
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 321
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 322
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 323
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 324
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 325
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 326
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 327
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 328
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 329
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 330
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 331
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 332
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 333
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 334
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 335
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 336
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 337
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 338
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 339
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 340
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 341
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 342
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 343
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 344
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 345
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 346
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 347
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 348
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 349
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 350
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 351
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 352
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 353
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 354
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 355
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 356
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 357
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 358
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 359
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 360
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 361
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 362
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 363
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 364
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 365
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 366
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 367
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 368
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 369
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 370
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 371
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 372
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 373
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 374
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 375
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 376
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 377
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 378
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 379
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 380
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 381
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 382
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 383
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 384
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 385
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 386
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 387
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 388
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 389
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 390
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 391
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 392
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 393
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 394
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 395
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 396
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 397
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 398
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 399
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 400
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 401
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 402
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 403
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 404
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 405
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 406
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 407
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 408
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 409
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 410
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 411
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 412
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 413
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 414
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 415
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 416
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 417
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 418
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 419
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 420
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 421
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 422
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 423
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 424
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 425
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 426
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 427
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 428
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 429
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 430
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 431
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 432
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 433
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 434
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 435
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 436
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 437
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 438
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 439
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 440
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 441
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 442
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 443
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 444
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 445
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 446
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 447
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 448
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 449
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 450
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 451
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 452
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 453
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 454
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 455
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 456
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 457
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 458
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 459
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 460
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 461
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 462
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 463
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 464
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 465
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 466
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 467
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 468
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 469
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 470
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 471
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 472
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 473
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 474
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 475
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 476
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 477
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 478
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 479
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 480
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 481
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 482
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 483
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 484
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 485
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 486
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 487
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 488
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 489
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 490
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 491
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 492
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 493
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 494
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 495
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 496
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 497
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 498
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 499
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 500
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 501
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 502
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 503
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 504
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 505
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 506
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 507
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 508
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 509
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 510
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 511
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 512
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 513
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 514
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 515
Suggested Citation:"6 Cancer." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 516

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

6 Cancer Cancer is the second-leading cause of death in the United States. Among men 50–64 years old, the group that includes most Vietnam veterans (see Table 6-1), the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). About 564,830 Americans of all ages were expected to die from cancer in 2006—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2006). This chapter summarizes and presents 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), 2,4,5- trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. If a new study reports on only a single type of cancer and does not revisit a previously studied population, its design information is summarized here with its results; design information on all other new studies can be found in Chapter 4; Appendix C contains cumulative tables that summarize studies that looked at multiple endpoints or involved repeatedly investigated populations that have contributed evidence to this series of reports. In an evaluation of a possible connection between herbicide exposure and risk of cancer, how exposures of study subjects were assessed is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapter 5, there is a great variety in detail and accuracy of exposure as- sessment among studies. A few studies used biologic markers of exposure, such as the presence of a compound in serum or tissues; some developed an index of exposure from employment or activity records; and others used surrogate mea- 261

262 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans 2004–2005 (numbers in thousands) Vietnam Era Vietnam Theater Ages Group (Years) N (%) N (%) All ages 7,934 3,853 49 133 (1.6) 32 (0.1) 50–54 1,109 (13.8) 369 (9.4) 55–59 3,031 (37.6) 1,676 (43.1) 60–64 2,301 (28.5) 1,090 (28.0) 65–69 675 (8.4) 280 (7.2) 70–79 511 (6.3) 322 (8.3) 80 178 (2.2) 83 (2.1) SOURCE: Table 3-3 (IOM, 1994), updated by 15 years. sures of exposure, such as presence in a geographic locale when herbicides were used. As noted in Chapter 2, inaccurate assessment of exposure can obscure the relationship between exposure and disease. Each section on a type of cancer opens with background information, includ- ing data on its incidence in the general US population and known or suspected risk factors. Cancer-incidence data on the general US population are included in the background material to provide a context for consideration of cancer risk in Vietnam veterans; the figures presented are estimates for the entire US popula- tion, however, not predictions for the Vietnam-veteran cohort. The incidence figures in this update are adapted to the demographic patterns defined by the 2000 US census data. The data reported are for 1998–2002, the most recent data set available (NCI, 2006). Incidence data are given for all races combined and separately for blacks and whites. The age range of 50–64 years now includes about 80 percent of Vietnam-era veterans, so incidences are presented for three 5-year age groups: 50–54 years, 55–59 years, and 60–64 years. The data were collected for the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute of the National Institutes of Health and are cat- egorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostatic cancer is about 4.3 times as high in men who are 60–64 years old than in men 50–54 years old; it is about twice as high in blacks 50–64 years old as in whites in the same age group (NCI, 2006). Many factors can influence incidence, including behavior (such as tobacco and alcohol use and diet), genetic predisposition, and medical history. Those factors can make someone more or less likely than the average to contract a given kind of cancer; they also need to be taken into account in epidemiologic studies of the possible contributions of the compounds of interest. The body of each section on a specific type of cancer includes a summary of the findings described in the previous Agent Orange reports: Veterans and

CANCER 263 Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003); and Update 2004 (IOM, 2005). That is fol- lowed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. Where appropri- ate, the literature is discussed by exposure type (occupational, environmental, or service in Vietnam). Each section ends with the committee’s conclusion regard- ing the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2. As explained in the following paragraphs, this committee has slightly modified the format in which it has satisfied the other two aspects of its charge. Biologic plausibility corresponds to the third element of the committee’s congressionally mandated statement of task. In previous updates, it had been discussed in the conclusion section for each health outcome after a statement of the committee’s judgment about the adequacy of the epidemiologic evidence of an association between exposure to the compounds of interest and the outcome. In fact, the degree of biologic plausibility itself influences whether the commit- tee perceives positive findings to be indicative of a pattern of association or the product of statistical fluctuations. To provide the reader with a more logical se- quence, in this update sections on biologic plausibility have been placed between the presentation of epidemiologic evidence and the synthesis of the evidence, which leads to the committee’s conclusion about the adequacy of the evidence to support an association. Information on biologic mechanisms that could contribute to the generic (rather than tissue- or organ-specific) carcinogenic potential of the compounds of interest is summarized in the section on biologic plausibility that precedes the synopsis of conclusions for the entire chapter. It distills toxicologic information concerning the mechanisms by which the compounds of interest affect carcino- genesis, as presented in more detail in Chapter 3; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in the chapter’s sections on particular cancer types, the generic information is implicit, and only toxicologic information peculiar to carcinogenesis at the site in question has been presented. Considerable uncertainty remains about the magnitude of potential risk posed by exposure to the compounds of interest. Many of the occupational, environ- mental, and veterans studies reviewed by the committee did not control fully for important confounders. There is not enough information about individual Viet- nam veterans to compare with exposures presented in scientific research studies. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the compounds of interest. Previous reports in the VAO series have had a rather formulaic statement to that effect as the third

264 VETERANS AND AGENT ORANGE: UPDATE 2006 entry in the conclusion section for each cancer type, corresponding to the second element in the committee’s statement of task as dictated by the congressional mandate. The (at least currently) insurmountable problems of deriving meaning- ful estimates of the risks of various health outcomes to Vietnam veterans are explained in Chapter 1 and the summary of this report, but the point is no longer reiterated for every health outcome addressed. AN EXHAUSTIVE AND UNAMBIGUOUS SYSTEM FOR ADDRESSING CANCER TYPES The Department of Veterans Affairs (VA) requested that the present commit- tee ensure that evaluations of the possibility of associations between exposures to the compounds of interest and various types of cancer be framed in such a fashion that a corresponding conclusion would be available for any type of cancer that might be diagnosed in a veteran and that it would be clear which conclusion would be applicable when a veteran filed a claim. VA also expressed concern that the episodic nature of the VAO series may have interfered with recognition and evaluation of cumulatively usable amounts of epidemiologic information on some uncommon cancers; in particular, VA asked for a focused examination of available information on cancer of the tonsil and acute myelogenous leukemia (AML). The committee therefore screened the studies that contributed results on the cancer types discussed in prior updates for results on tonsil cancer, AML, and other uncommon sites while gaining an over- view of how cancer sites are typically grouped to report findings. VA had indicated that a grouping system for reporting the committee’s con- clusions based on the International Classification of Diseases (ICD) codes would be appropriate to match the diagnostic information presented in veterans’ claims. ICD is used to code and classify mortality data from death certificates. ICD CM (clinical modification) is used to code and classify morbidity data from medical records, hospital records, and surveillance surveys. The 10th edition (ICD-10) came into use in 1999 and constitutes a marked change from the previous four versions that evolved into the ninth edition (ICD-9). ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research re- viewed in this series, it has been used when codes are given for a specific health outcome. The first modification made in this update toward addressing VA’s request was to change the order in which cancer types are discussed, which had evolved from the original VAO report. The more systematic order of major and minor categories of cause of death for cancer sites established by the National Institute for Occupational Safety and Health (NIOSH) is now followed with minor ex- ceptions. The NIOSH groups map the full range of ICD-9 codes for malignant neoplasms (140–208), and this somewhat coarser gradient has been adopted as an exhaustive organizing principle for the present chapter. Appendix B discusses

CANCER 265 the issue in more detail and delineates the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (Table B-1); the groupings for mortal- ity are largely congruent with those of the SEER program for cancer incidence (see Table B-2, which presents equivalences between the ICD-9 and ICD-10 systems). The groups provide a comprehensive framework for software routinely used by epidemiologists to generate expected values based on the demographics of the cohort being studied and have well-documented correspondence with the more detailed ICD coding system in its successive iterations (Robinson et al., 2006). When conditions reported on in epidemiologic research are specified in ICD ranges, the specificity may not be as refined as might be desired for some purposes, and errors of misclassification in the research process cannot be ex- cluded, but the grouping intended is unambiguous. This rearrangement following a largely anatomic sequence should make locating a particular cancer easier for readers and facilitated the committee’s iden- tification of ICD codes for malignancies that had not been explicitly addressed in previous updates (as noted in italics in Table B-1). VAO reports’ default cat- egory for any health outcome for which no epidemiologic research findings have been recovered has always been “inadequate evidence” of association, which in principle is applicable to specific cancers. In this update, it still is the case that failure to review a specific cancer or other condition separately reflects the paucity of information, so there is indeed inadequate or insufficient information to categorize such a disease outcome. However, in response to VA’s request and in light of our review of how “rare cancers” are grouped or presented when they do have reported results, we state here how each of these previously overlooked ICD codes will be treated in this and future updates: • ICD-9 149, other buccal cavity and pharynx—routinely included in full buccal cavity and pharynx range, 140–149. • ICD-9 152, small intestine—rarely reported individually; to be encom- passed in conclusions for colorectal cancers. • ICD-9 156, gallbladder and extrahepatic bile ducts—to be tracked under hepatobiliary cancers. • ICD-9 158–159, retroperitoneum and other and unspecified digestive cancers—rarely reported individually; to be encompassed in conclusions for colorectal cancers. • ICD-9 162.0, trachea—intended grouping with lung and bronchus has not always been explicitly stated. • ICD-9 163, pleura—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with mediastinum and other and unspecified respiratory cancers. • ICD-9 164.0, thymus—to be considered with thyroid and other endocrine cancers. • ICD-9 164.2–164.9, mediastinum—rarely reported individually and not

266 VETERANS AND AGENT ORANGE: UPDATE 2006 as yet seen for the chemicals of interest; would be considered with pleura and other and unspecified respiratory cancers. • ICD-9 165, other and unspecified respiratory cancers—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with pleura and mediastinum as other respiratory cancers. • ICD-9 179, unspecified parts of uterus—to be considered with female reproductive system. • ICD-9 181, placenta—to be considered with female reproductive system. • ICD-9 183.2–183.9, fallopian tube and other uterine adnexa—to be con- sidered with female reproductive system. • ICD-9 184, other female genital organs—to be considered with female reproductive system. • ICD-9 187, penis and other male genital organs—to be considered with testis as other male reproductive organs (excluding prostate). • ICD-9 189.3–189.9, urethra, paraurethral glands, and other and unspeci- fied urinary—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with bladder cancer. • ICD-9 190, eye—to be considered with brain and other parts of nervous system. • ICD-9 193, thyroid—to be considered with thymus and other endocrine cancers. • ICD-9 194, other endocrine cancers—to be considered with thyroid and thymus as endocrine cancers. • ICD-9 195, other and ill-defined sites—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with other and unspecified cancers. • ICD-9, 196–198, stated or presumed to be secondary of specified sites— rarely reported individually and not as yet seen for the chemicals of inter- est; would be considered with other and unspecified cancers. • ICD-9, 199, site unspecified—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with other and unspecified cancers. This committee’s search of previously reviewed studies for results on ton- sil cancer and AML also identified sets of previously considered papers with reported findings specifically on lip cancer (ICD-9 140) and on tongue cancer (ICD-9 141), which both fall within the range for cancers of the oral (buccal) cavity. The current update includes separate sections discussing the site-specific results. In future updates, however, findings for these sites will be tracked on the results tables for the broader grouping that contains them: buccal cavity, nose, and pharynx (ICD-9 140–149, 160) for tonsil, tongue, and lip, and leukemias (ICD- 9 204–208) for AML. For the digestive cancers, in future updates esophageal,

CANCER 267 stomach, colorectal, hepatobiliary, and pancreatic cancers will be broken out into sections with individual conclusions. Care will be taken to specify as precisely as possible in results tables when findings are being reported for a subsite of a particular grouping. ORAL, NASAL, AND PHARYNGEAL CANCER Oral, nasal, and pharyngeal cancers (ICD-9 140–149, 160) are found in many anatomic subsites, including the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and hard and soft palate) (ICD-9 140–145), oropharynx (ICD-9 146), nasopharynx (ICD-9 147), hypopharynx (ICD-9 148), other buccal cavity and pharynx (ICD-9 149), and nasal cavity and paranasal sinuses (ICD-9 160). Although those sites are anatomically diverse, cancers that occur in the nasal cavity, oral cavity, and pharynx are for the most part similar in descriptive epidemiology and risk factors. The exception is cancer of the nasopharynx, which has a different epidemiologic profile. The American Cancer Society (ACS) estimated that about 30,990 men and women would receive a diagnosis of oral or pharyngeal cancer in the United States in 2006 and 7,430 men and women would die from these diseases (Jemal et al., 2006). Less than 10 percent as many cancers originate in the nasal cavity. Most oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Naso- pharyngeal carcinoma (NPC) is the most common malignant tumor of the naso- pharynx; it is relatively rare in the United States, where it accounts for about 0.25 percent of all cancers. There are three types of NPC: keratinizing squamous- cell carcinoma, nonkeratinizing carcinoma, and undifferentiated carcinoma. The average annual incidences reported in Table 6-2 show that men are at greater risk than women for those cancers and that the incidences increase with age, although there are few cases, and care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (Hayes, 1997), wood dust (Demers et al., 1995), and formaldehyde (Blair and Kazerouni, 1997). Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Studies evaluated previously and in this report are summarized in Table 6-3.

268 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral Cavity and Pharynx, and Oropharynx Cancers in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Nose, Nasal Cavity, and Middle Ear: Men 1.2 1.1 1.2 1.6 1.5 1.8 2.0 2.0 3.0 Women 0.6 0.6 0.4 1.0 1.1 0.3 1.1 1.1 1.6 Nasopharynx: Men 1.8 1.0 1.7 2.3 1.5 1.8 3.1 1.6 4.5 Women 0.7 0.3 0.8 0.6 0.3 0.3 1.2 0.6 0.4 Oral Cavity and Pharynx: Men 28.4 27.6 42.0 37.2 36.4 53.1 47.9 47.3 66.1 Women 9.2 8.7 11.6 12.6 12.7 15.5 17.3 17.5 19.0 Oropharynx: Men 1.0 0.8 3.1 1.1 1.0 3.2 2.2 2.0 6.5 Women 0.1 0.1 0.2 0.6 0.5 1.8 0.2 0.2 0.0 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational International Agency for Research on Cancer (IARC) cohort of 60,468 pulp and paper industry workers. A job–exposure matrix (JEM) was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine compounds (which would include TCDD). Deaths from cancers of the oral cavity and pharynx were signifi- cantly fewer among those who had been exposed to nonvolatile organochlorine compounds (n 15; standardized mortality ratio [SMR] 0.51, 95% confidence interval [CI] 0.29–0.85) but not among those who had never been exposed (n 33; SMR 0.92, 95% CI 0.63–1.29). Alavanja et al. (2005) reported that among the private pesticide applicators in the Agricultural Health Study (AHS), there were 66 cases of buccal-cavity can- cer, which represented a significant deficit compared with the general population (standardized incidence ratio [SIR], 0.66, 95% CI 0.51–0.83). The correspond- ing results for commercial pesticide applicators were based on much smaller numbers of cases, so the confidence interval on the SIR was wide. Among the spouses of private applicators, the SIR for buccal cavity cancer was 0.73 (95% CI 0.40–1.22) on the basis of 14 cases. Nasal and pharyngeal cancers were not

CANCER 269 TABLE 6-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer Estimated Exposed Relative Risk Reference Study Population a,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds (oral cavity and pharynx) Never 33 0.9 (0.6–1.3) Ever 15 0.5 (0.3–0.9) Alavanja US Agriculture Health Study—incidence (buccal cavity) et al., 2005 Private applicators (men and women) 66 0.7 (0.5–0.8) Lip 25 1.4 (0.9–2.1) Spouses of private applicators ( 99% women) 14 0.7 (0.4–1.2) Lip 2 1.4 (0.2–5.1) Commercial applicators (men and women) 5 0.9 (0.3–2.2) Lip 3 2.7 (0.6–8.0) Blair et al., US Agriculture Health Study (buccal cavity and pharynx) 2005a Private applicators (men and women) 5 0.3 (0.1–0.7) Spouses of private applicators ( 99% women) 0 0.0 (0–25.4) ’t Mannetje Phenoxy herbicide producers (men and women) (ICD-9 et al., 2005 140–149) 2 2.8 (0.3–9.9) Lip (ICD-9 140) 0 * Mouth (ICD-9 141–145) 2 5.4 (0.7–20) Oropharynx (ICD-9 146) 0 * Nasopharynx (ICD-9 147) 0 0.0 (0.0–42) Hypopharynx and other (ICD-9 148–149) 0 * Phenoxy herbicide sprayers ( 99% men) (ICD-9 140–149) 1 1.0 (0.0–5.7) Lip (ICD-9 140) 0 * Mouth (ICD-9 141–145) 0 0.0 (0.0–7.5) Oropharynx (ICD-9 146) 0 * Nasopharynx (ICD-9 147) 1 8.3 (0.2–46) Hypopharynx and other (ICD-9 148–149) 0 * Torchio Italian licensed pesticide users et al., 1994 Buccal cavity and pharynx 18 0.3 (0.2–0.5) Reif et al., New Zealand forestry workers—incidence 1989 Buccal cavity 3 0.7 (0.2–2.2) Nasopharyngeal 2 5.6 (1.6–19.5) Studies Reviewed in Update 2004 Nordby Norwegian farmers born 1925–1971—incidence, lip et al., 2004 Reported pesticide use * 0.7 (0.4–1.0) Swaen Dutch licensed herbicide applicators et al., 2004 Nose 0 — Mouth and pharynx 0 — continued

270 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-3 Continued Estimated Exposed Relative Risk Reference Study Population a,b Casesc (95% CI)c Studies Reviewed in Update 2000 Caplan Case–control study of US men born 1929–1953, all 70 et al., 2000 nasal cancers (carcinomas, plus 11 lymphomas and 5 sarcomas) from CDC (1990a) study population Selected landscaping and forestry occupations 26 1.8 (1.1–3.1) Living or working on farm 23 0.5 (0.3–0.8) Herbicides or pesticides 19 0.7 (0.4–1.3) Phenoxy herbicides 5 1.2 (0.4–3.3) Studies Reviewed in Update 1998 Hooiveld Workers at Dutch chemical factory (lip, oral cavity, et al., 1998 pharynx) All working any time 1955–1985 1 2.3 (0.1–12.4) Cleaned up 1963 explosion 1 7.1 (0.2–39.6) Rix et al., Danish men and women paper mill workers 1998 Buccal cavity (ICD-7 140–144) Men 24 1.0 (0.7–1.5) Women 4 1.5 (0.4–3.8) Pharynx (ICD-7 145–149) Men 15 2.0 (1.1–3.3) Women 2 2.1 (0.2–7.6) Tonsil cancers among pharyngeal cancers 11 Kogevinas IARC cohort (men and women)—Workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol Oral cavity and pharynx cancer (ICD-9 140–149) 26 1.1 (0.7–1.6) Exposed to TCDD 22 1.3 (0.8–2.0) Not exposed to TCDD 3 0.5 (0.1–1.3) Nose and nasal sinuses cancer (ICD-9 160) 3 1.6 (0.3–4.7) Exposed to TCDD 0 0.0 (0.0–3.5) Not exposed to TCDD 3 3.8 (0.8–11.1) Studies Reviewed in Update 1996 Becher German phenoxy herbicide production workers (included et al., 1996 in the IARC cohort) Buccal cavity, pharynx (ICD-9 140–149) 9 3.0 (1.4–5.6) Tongue 3 * Floor of mouth 2 * Tonsil 2 * Pharynx 2 * Asp et al., Finnish herbicide applicators 1994 Buccal and pharynx (ICD-8 140–149) Incidence 5 1.0 (0.3–2.3) Mortality 0 0.0 (0.0–3.0) “Other Respiratory” (ICD-8 160, 161, 163)—nose, larynx, pleura Incidence 4 1.1 (0.3–2.7) Mortality 1 0.5 (0.0–2.9)

CANCER 271 TABLE 6-3 Continued Estimated Exposed Relative Risk Reference Study Population a,b Casesc (95% CI)c Studies Reviewed in VAO Blair et al., White male farmers from 23 state—deaths 1984–1988 1993 Lip 21 2.3 (1.4–3.5) Ronco Italian farmers (lip, tongue, salivary glands, mouth, et al., 1992 pharynx)—mortality Self-employed 13 0.9 (*) Employees 4 0.5 (*) Danish self-employed farmers—incidence Lip 182 1.8 (p 0.05) Tongue 9 0.6 (*) Salivary glands 13 0.9 (*) Mouth 14 0.5 (p 0.05) Pharynx 13 0.3 (p 0.05) Nasal cavities and sinuses 11 0.6 (*) Danish farming employees—incidence Lip 43 2.1 (p 0.05) Tongue 2 0.6 (*) Salivary glands 0 0.0 (*) Mouth 0 0.0 (p 0.05) Pharynx 9 1.1 (*) Nasal cavities and sinuses 5 1.3 (*) Saracci IARC cohort—exposed subcohort (men and women) et al., 1991 Buccal cavity and pharynx (ICD-8 140–149) 11 1.2 (0.6–2.1) Nose and nasal cavities (ICD-8 160) 3 2.9 (0.6–8.5) Zober BASF Aktiengesellschaft accident cohort—33 cancers et al., 1990 among 247 workers at 34-yr follow-up Squamous-cell carcinoma of tonsil 1 * Wiklund Licensed Swedish pesticide applicators— et al., incidence 1989a Lip 14 1.8 (1.0–2.9) Coggon British MCPA production workers (included in the IARC et al., 1986 cohort) Lip (ICD-9 140) 0 * Tongue (ICD-9 141) 1 1.1 (0.0–6.2) Pharynx (ICD-9 146–149) 1 0.5 (0.0–3.0) Nose (ICD-9 160) 3 4.9 (1.0–14.4) Robinson Northwestern US paper and pulp workers et al., 1986 Buccal cavity and pharynx (ICD-7 140–148) 1 0.1 (0.0–0.7) Nasal (ICD-7 160) 0 —* Wiklund, Swedish men and women agricultural 1983 workers—incidence Lip 508 1.8 (1.6–2.1) Tongue 32 0.4 (0.2–0.6) Salivary glands 68 1.0 (0.7–1.4) Mouth 70 0.6 (0.5–0.8) Throat 84 0.5 (0.4–0.7) Nose and nasal sinuses 64 0.8 (0.6–1.2) continued

272 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-3 Continued Estimated Exposed Relative Risk Reference Study Population a,b Casesc (95% CI)c Hardell Residents of northern Sweden (44 nasal and 27 naso- et al., 1982 pharyngeal cancers) Phenoxy acid exposure 8 2.1 (0.9–4.7) Chlorophenol exposure 9 6.7 (2.8–16.2) Burmeister, Iowa farmers—deaths 1971–1978 1981 Lip 20 2.1 (p 0.01) ENVIRONMENTAL Studies Reviewed in VAO Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Buccal cavity (ICD-9 140–149) Zone B—Men 6 1.7 (0.8–3.9) Women 0 —* Zone R—Men 28 1.2 (0.8–1.7) Women 0 —* Nose and nasal cavity (ICD-9 160) Zone R—Men 0 —* Women 2 2.6 (0.5–13.3) VIETNAM VETERANS New Studies ADVA, Australian Vietnam veterans vs Australian 2005a population—incidence Head and neck 247 1.5 (1.3–1.6) Navy 56 1.6 (1.1–2.0) Army 174 1.6 (1.3–1.8) Air Force 17 0.9 (0.5–1.5) ADVA, Australian Vietnam veterans vs Australian 2005b population—mortality Head and neck 101 1.4 (1.2–1.7) Navy 22 1.5 (0.9–2.1) Army 69 1.5 (1.1–1.8) Air Force 9 1.1 (0.5–2.0) Nasal 3 0.8 (0.2–2.2) ADVA, Australian conscripted Army National Service Vietnam- 2005c era veterans: deployed vs non-deployed Head and neck Incidence 44 2.0 (1.2–3.4) Mortality 16 1.8 (0.8–4.3) Nasal Mortality 0 0.0 (0.0–48.2) Boehmer Follow-up of CDC Vietnam Experience Cohort (ICD-9 et al., 2004 140–149) 6 *

CANCER 273 TABLE 6-3 Continued Estimated Exposed Relative Risk Reference Study Population a,b Casesc (95% CI)c Studies Reviewed in Update 2004 Akhtar White AFHS subjects vs national rates (buccal cavity) et al., 2004 Ranch Hand veterans Mortality—all 0 0.0* Incidence—all 6 0.9 (0.4–1.9) With tours between 1966–1970 6 1.1 (0.5–2.3) Comparison veterans Mortality—all 1 0.5* Incidence—all 5 0.6 (0.2–1.2) With tours between 1966–1970 4 0.6 (0.2–1.4) Studies Reviewed in Update 2000 AFHS, Air Force veterans participating in 1997 exam cycle, 2000 Ranch Hands vs Comparisons Oral cavity, pharynx, and larynx 4 0.6 (0.2–2.4) Studies Reviewed in Update 1998 CDVA, Australian Vietnam veterans vs Australian 1997a population—incidence Lip (ICD-9 140) 0 * Nasopharyngeal cancer (ICD-9 147) 2 0.5 (0.1–1.7) Nasal cavities (ICD-9 160) 2 1.2 (0.1–4.1) CDVA, Australian conscripted Army National Service Vietnam- 1997b era veterans—deployed vs non-deployed Nasopharyngeal cancer 1 1.3 (0.0– 10) Nasal cavities 0 0 (0.0– 10) Vistainer Michigan Vietnam veterans (lip, oral cavity, pharynx) et al., 1995 Non-blacks 11 1.1 (0.5–1.9) Studies Reviewed in VAO CDC, Case–control study of US men born 1929–1953 1990a 89 Nasopharyngeal carcinomas Vietnam service 3 0.5 (0.2–1.8) 62 Nasal carcinomas Vietnam service 2 0.7 (0.2–2.9) ABBREVIATIONS: AFHS, Air Force Health Study; CDC, Centers for Disease Control and Pre- vention; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Edition; MCPA, methyl-4-chlorophenoxyacetic acid. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort.

274 VETERANS AND AGENT ORANGE: UPDATE 2006 explicitly reported in the study, but the portion of them that were specifically lip cancers was analyzed (see below). Using death as the outcome among participants in the AHS, Blair et al. (2005a) reported five deaths from buccal-cavity and pharyngeal cancers com- bined in the private applicators, indicating a significant reduction in mortality (SMR 0.3, 95% CI 0.1–0.7). There were no deaths from these cancers among spouses of applicators. ’t Mannetje et al. (2005) reported results for lip, oral cavity, and pharynx combined (ICD-9 140–149), which represented two deaths from cancer of un- specified parts of the mouth (ICD-9 141–145) observed among the production workers and one from nasopharyngeal cancer (ICD-9 147) observed among the sprayers. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pes- ticide users from the Piedmont region, which the Italian National Institute of Statistics reports as having high herbicide use, especially of 2,4-D and (4-chloro- 2-methylphenoxy) acetic acid (MCPA). The risk estimate for cancer of the buccal cavity and pharynx was significantly reduced (18 cases; SMR 0.34, 95% CI 0.2–0.5). The authors suggested that the healthy-worker effect contributed to the observation of reduced mortality. Reif et al. (1989) performed a series of case–control analyses on a sample of 19,904 men entered into the New Zealand Cancer Registry from 1980–1984 with an occupation specified. They focused on the 134 registrants for whom forestry worker (presumed to be exposed to phenoxyherbicides and chlorophenols) was the most recent occupation. The three forestry workers among the 649 cases with cancer of the buccal cavity did not constitute an excess (odds ratio [OR] 0.71, 95% CI 0.23–2.19). However, two forestry workers among the 49 cases of naso- pharyngeal cancer (OR 5.56, 95% CI 1.59–19.48) did represent a significantly increased risk. Environmental Studies No new environmental studies concerning exposure to the compounds of in- terest and oral, nasal, or pharyngeal cancers were published since Update 2004. Vietnam-Veteran Studies The report titled Cancer Incidence in Australian Vietnam Veterans Study 2005 (ADVA, 2005a) noted 247 head and neck cancers, including cancers of the tongue, gum, mouth, palate, salivary glands, tonsil, oropharynx, and nasopharynx. There was a significant increase in the incidence of head and neck cancers (SIR 1.48, 95% CI 1.29–1.66). The results were equivalent in Navy veterans (SIR 1.55, 95% CI 1.14–1.95) and Army veterans (SIR 1.55, 95% CI 1.32–1.78), but the association was considerably weaker in Air Force veterans (SIR 0.93, 95% CI 0.54–1.49).

CANCER 275 On the basis of 101 observed deaths from head and neck cancer, The Third Australian Vietnam Veterans Mortality Study 2005 (ADVA, 2005b) reported a significant increase in the Vietnam-veteran cohort (SMR 1.44, 95% CI 1.16– 1.73). There were 69 cases of head and neck cancer in the Army veterans (SMR 1.49, 95% CI 1.14–1.84), 22 cases in the Navy veterans (SMR 1.49, 95% CI 0.87–2.10), and 9 in the Air Force veterans (SMR 1.09, 95% CI 0.49–2.03). Those cancers were previously found to be somewhat increased in an earlier mortality study of the same cohort; CDVA (1997a) reported an SMR of 1.2 (95% CI 0.2–4.4) for nasal cancers. In commenting on the statistically significant roughly 50 percent increase in both incidence and mortality from head and neck cancers among the Austra- lian Vietnam veterans, the authors noted that these cancers are associated with cigarette-smoking and alcohol use, but neither of these risk factors was measured or adjusted for in the reports. They commented that alcohol consumption is higher among servicemen than in the general population and that if cigarette-smoking were increased in this cohort, it also could explain some of the observed increase in head and neck cancers relative to the incidence in the general population. Another Australian study (ADVA, 2005c), which compared deployed male Army National Service veterans with their non-deployed Vietnam-era counter- parts, also reported on head and neck cancers. There were 44 cases among the deployed and 28 cases among the non-deployed, for an increased relative risk (RR) of 2.02 (95% CI 1.23–3.37) in this design aimed at accounting for factors in which the military subjects differed from the general Australian populace. With 16 deaths among the deployed and 11 among the non-deployed, the findings on mortality from head and neck cancers were more equivocal (RR 1.82, 95% CI 0.79–4.33). Mortality due to nasal cancer was also listed in the Australian reports, but the numbers observed were too small for estimation of any stable statistics: three cases in all the Australian Vietnam veterans (ADVA, 2005b) and no deaths from nasal cancer in the deployed and one in the non-deployed (ADVA, 2005c). In the mortality update through 2000 on the Centers for Disease Control and Prevention (CDC) Vietnam Experience Study (VES) comparing deployed and non-deployed Vietnam-era veterans, Boehmer et al. (2004) reported six cases of lip, oral-cavity, or pharynx cancer (ICD-9 140–149) in the deployed and three in the non-deployed, for a crude RR of 2.0. The researchers did not consider the data sufficient for the calculation of risk statistics unless there were at least 10 deaths from cancer of a given type. Biologic Plausibility A recent National Toxicology Program (NTP) study (Yoshizawa et al., 2005a) reported an increase in the incidence of gingival squamous-cell carcinoma in fe-

276 VETERANS AND AGENT ORANGE: UPDATE 2006 male rats treated orally (by gavage) with TCDD at 100 ng/kg 5 days/week for 104 weeks. Incidences of gingival squamous-cell hyperplasia were significantly increased in all groups treated at 3–46 ng/kg. In addition, squamous-cell carci- noma in the oral mucosa of the palate was increased. Increased neoplasms of the oral mucosa were previously observed and described as carcinomas of the hard palate and nasal turbinates (Kociba et al., 1978). Kociba et al. (1978) also reported a small increase in the incidence of tongue squamous-cell carcinoma. A similar 2-year study performed in female rats failed to reveal a pathologic effect of TCDD on nasal tissues (Nyska et al., 2005). The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis The new occupational studies of cancers of the oral and nasal cavities or pharynx were generally small and so yielded unstable estimates of risk. Integra- tion of the evidence on this set of cancers is challenging because different studies group cases differently. The significant results found in the AHS population of pesticide applicators (the incidence of buccal-cavity cancers in private applicators in the Alavanja study and mortality from buccal-cavity and pharyngeal cancers in the Blair study) were in the direction of deficits rather than excess risk associated with exposure. Studies on Australian Vietnam veterans showed some increases in risk, but the results were not adjusted for cigarette-smoking or alcohol use, both of which are known risk ractors. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and oral, nasal, or pharyngeal cancers. At the request of VA, the committee attempted to ensure that the conditions making up the full array of relevant cancer types had been reviewed and reported on with the greatest appropriate degree of specificity. The results suggested that some of the head and neck cancers that have been considered together in this section starting with the original VAO report might merit more individualized consideration. Such a review is complicated, however, by the fact that a specific cancer type may have been implicitly subsumed in broader groupings, particu- larly when no cases of the specific type were observed in a given study. The fol- lowing subsections, therefore, address the cumulative evidence that lip cancer, tongue cancer, or tonsil cancer might individually be associated with exposure to the herbicides used in Vietnam.

CANCER 277 Lip Cancer In the committee’s review, at VA’s request, for cancers that may have been overlooked, a number of reported results were found specifically on lip cancer (ICD-9 140). They are evaluated as a group in this section, and information pecu- liar to lip cancer has been incorporated into Table 6-3, which presents the overall epidemiologic findings on oral, nasal, and pharyngeal cancers. In addition to the risk factors for oral and pharyngeal cancers discussed above, exposure to sunlight is a risk factor for lip cancer. Conclusions from VAO and Updates This update considers lip cancer independently for the first time. Prior up- dates considered lip cancer only as a possible component of the various types of cancer grouped as oral, nasal, and pharyngeal cancers, the evidence on which has been judged to be inadequate to support an association with exposure to the herbicides used in Vietnam. Summary of the Epidemiologic Literature Occupational Studies Burmeister (1981) reported cancer mortality from 1971 to 1978 in Iowa male farmers and non-farmers. Farming was defined according to the usual occupation as indicated on the death certificates. Both SMRs and proportional mortality ratios (PMRs) were computed. The SMR for lip cancer was 2.06 (p 0.01); the PMR for white male farmers less than 65 years old was 4.65 (not significant), and the PMR for white male farmers 65 years old and older was 1.51 (p 0.05). The combined PMR over all ages was 1.62 (p 0.01). There were 20 lip-cancer deaths in farmers and 11 in non-farmers. There was no specific exposure information on the participants in the study, beyond that inferred from the indication of usual occupation on the death certificates. Wiklund (1983) linked Sweden’s National Cancer Registry with information from the 1960 census. The census categorization of occupation was determined for tumors diagnosed in the period 1961–1973. Some 19,490 persons were regis- tered as having agriculture as their economic activity although no direct pesticide or herbicide exposure is necessarily inferred. The results showed 508 cases of lip cancer, leading to an SIR of l.83 (95% CI 1.62–2.05); similarly, for men alone the SIR was 1.82. Wiklund et al. (1989a) studied 20,245 licensed Swedish pesticide applicators whose licenses were issued in 1965–1976. The vast majority of cohort members were men. Overall, the cohort had a significantly decreased SIR for all cancers combined and for several specific cancers. There were no statistically significant increases in risk for any cancers or any time trends. For lip cancer, there were 14 observed cases (SIR 1.75, 95% CI 0.96–2.94).

278 VETERANS AND AGENT ORANGE: UPDATE 2006 Blair et al. (1993) analyzed deaths occurring in 23 states in 1984–1988. PMRs were calculated by sex and race for farmers, who were people whose death certificates indicated farming as their usual occupation and agricultural crop products or livestock as their industry. White men had a PMR of 2.31 (95% CI 1.43–3.53) on the basis of 21 lip-cancer cases. The findings for other race–sex groups were not significant and consisted of only one case. The authors noted that their mortality risk estimates in general were more likely to be underestimated than overestimated because of misclassification of disease and occupation. Those effects are thought to be more severe than any increase in risk associated with the use of proportional rather than absolute mortality analyses. It should be noted that this study has no specific data on pesticide or herbicide exposures beyond an indirect inference associated with the death-certificate occupation. Nordby et al. (2004) reported on a cohort study of lip cancer in farmers in Norway born in 1925–1971. They were followed until 1999 to identify incident cases of lip cancer by using the national cancer registry in Norway. Exposure of cohort members was assessed through proxy measures, such as farm production, weather and fungal forecasts, and pesticide use (not peculiar to any particular agent). The results showed a statistically significantly reduced risk of lip cancer associated with exposure to pesticides. The lip-cancer rate among those not re- porting pesticide use was 4.9 per 100,000 person-years, and the corresponding figure for pesticide users was 3.7. A multivariate model was fitted to examine the effects of pesticide use and other factors, including grain farming, fungal forecasts, horses on the farm, and engagement of the farmer in the construction industry. The RR associated with pesticide use in this model was 0.7 (95% CI 0.4–1.0). The authors speculate that the reduction in risk might be associated with exposure to immunosuppressive mycotoxins, in which case pesticides would reduce the farmers’ burden of exposure by reducing mold growth. There may also be effects of sun exposure in this occupational group. Among the private pesticide applicators in the AHS, Alavanja et al. (2005) report 25 cases of lip cancer (SIR 1.43, 95% CI 0.93–2.11). There were two lip-cancer cases in the spouses of private applicators and three in commercial ap- plicators; the SIR were modestly increased with very wide confidence intervals. Mortality from lip cancer was not reported in the companion AHS study (Blair et al., 2005b). Environmental Studies No new environmental studies concerning exposure to the compounds of interest and lip cancer were published since Update 2004. Vietnam-Veteran Studies The Australian veterans cohort study (CDVA, 1997a) reported that no deaths from lip cancer were observed. The updated study of mortality in Australian Vietnam veterans (ADVA, 2005b) does not mention lip cancer.

CANCER 279 Synthesis The studies reporting on lip cancer that were identified by the committee’s retrospective screen for results on rare cancers in the publications considered previously in the VAO series generally had very low specificity with respect to exposure to the compounds of interest. Exposure status was defined almost exclusively in terms of occupation, and even the determination of occupation usually could not be regarded as rigorous. In most instances, occupation was not stringently defined and was ascertained at only one time (for example, in a census or on a death certificate). Studies that use computer techniques to link records in comprehensive da- tabases, such as those matching entries in tumor registries with compendiums of national censuses, amass large samples that may have the effect of inflating power. Such investigations are useful for generating hypotheses, but suggestive findings must be replicated by studies with more refined designs that are capable of gathering more extensive information about the subjects to use in adjusting for confounders. The certainty of the diagnostic categories may also be dubious when infor- mation is culled directly from death certificates or other databases. For lip cancer, in particular, it is unclear to what extent this diagnostic category would overlap with non-melanoma skin cancers in the sources from which the information was gathered for the studies discussed here. For lip cancer, it would be important to adjust for smoking and sunlight exposure before inferring that agricultural chemicals (perhaps in the family of phenoxy herbicides) played a role in any observed association in an occupational group. Such adjustment was not part of the analyses conducted in the studies discussed here that reported increased risks of lip cancer in occupational groups that had theoretical exposure to the compounds of interest. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and lip cancer. Tongue Cancer In the committee’s review, at VA’s request, for cancers that may have been overlooked, a number of reported results were found specifically on tongue can- cer (ICD-9 141). They are evaluated as a group in this section, and information peculiar to tongue cancer has been incorporated into Table 6-3, which presents the overall epidemiologic findings on oral, nasal, and pharyngeal cancers.

280 VETERANS AND AGENT ORANGE: UPDATE 2006 Conclusions from VAO and Updates This update considers tongue cancer independently for the first time. Prior updates considered tongue cancer only as a possible component of the various types of cancer grouped as oral, nasal, and pharyngeal cancers, the evidence on which has been judged to be inadequate to support an association with exposure to the herbicides used in Vietnam. Summary of the Epidemiologic Literature Occupational Studies Among the 331,767 Swedish people who received a diagnosis of a malignant tumor in 1961–1973, Wiklund (1983) found 19,490 with agriculture indicated as their economic activity on the Swedish census. Direct pesticide or herbicide exposure cannot necessarily be inferred. The 32 cases of tongue cancer yielded a risk significantly below the null ratio of 1 (SIR 0.40, 95% CI 0.24–0.61). The SIR for men alone was 0.35. Coggon et al. (1986) described the mortality and cancer experience of work- ers at a factory that manufactured, formulated, and sprayed MCPA and other phe- noxy acid herbicides. Overall mortality in 5,784 men employed in the company during 1947–1975 was traced until the end of 1983 and was shown to be lower than that in the national population; the picture was similar for cancer mortal- ity. The single observed death due to tongue cancer—very close to the expected number—led to an SMR of 0.96 with a very wide CI. An adjustment for the overall difference between urban and rural mortality led to similar results. Green (1991) conducted a cohort mortality study of forestry workers at a public electric utility in Ontario; cohort members had worked for more than 6 months during 1950–1982 and were routinely exposed to herbicides. The general population was used as a comparison. There was no overall excess mortality compared with that in the reference population. Only a single death from tongue cancer was observed; no site-specific SMR was computed. The authors noted that members of the cohort were generally still young, and at the end of the study fol- low-up period most participants had not reached ages at which the incidence of cancer would usually increase. Consequently, this study may have had relatively low power. The specific pattern of herbicide use by Ontario Hydro (the study em- ployer) was described in some detail, but there are no direct linkages of exposure to individual study participants. Ronco et al. (1992) reported nine cases of tongue cancer among men self- employed as farmers in Denmark with an SIR of 0.58 and two cases among male farm employees with an SIR of 0.63; neither result is statistically significant. There were no incident cases of tongue cancer among Danish women. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and tongue cancer were published since Update 2004.

CANCER 281 Vietnam-Veteran Studies The Australian Veteran Cohort Study (CDVA, 1997a) investigated mortality in Australian veterans who had served in Vietnam. There were 17 deaths from tongue cancer, with a calculated SMR of 2.53. The standardized relative mortality ratio (SRMR), the SMR for a specific cancer site divided by the SMR for all other causes of death combined, was 2.34 (95% CI 1.46–3.84) and suggested a risk increase relative to the risk of other causes of death. Synthesis Interpretation of the evidence on tongue cancer is constrained by the group- ing of data on them with data on other oral cancers. Most of the studies with information on this specific tumor site observed only a small number of cases and therefore had unstable estimates of risk. Conclusion On the basis of its evaluation of the epidemiologic evidence reviewed ret- rospectively here on tongue cancer alone, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and tongue cancer. Tonsil Cancer VA asked that the committee undertake a focused examination of what information might be available on cancer of the tonsil (ICD-9 146.0–146.2), which constitutes a portion of the oropharynx (ICD-9 140). Tonsil cancer may also arise in proximal areas of the oral and throat region, including the soft palate (ICD-9 145.3), the adenoid and the pharyngeal tonsil in the posterior pharyngeal wall (ICD-9 147.1), the base of the tongue (ICD-9 141.0), and the lingual tonsil (ICD-9 141.6). Tonsil cancers are usually classified as squamous-cell carcinomas, but the cell types found in biopsy tissue occasionally lead oral pathologists to classify some as sarcomas or lymphomas (Mayo Clinic, 2007). Tonsil cancer is somewhat more common in men than in women, and smoking and alcohol may increase the risk. The committee screened the studies that contributed results on the cancer types discussed in prior updates for results on tonsil cancer. The committee’s findings are discussed below, and information peculiar to tonsil cancers has been incorporated into Table 6-3, which presents the overall epidemiologic findings on oral, nasal, and pharyngeal cancers.

282 VETERANS AND AGENT ORANGE: UPDATE 2006 Conclusions from VAO and Updates This update considers tonsil cancer independently for the first time. Prior updates considered tonsil cancer only as a possible component of the various types of cancer grouped as oral, nasal, and pharyngeal cancers, the evidence on which has been judged to be inadequate to support an association with exposure to the herbicides used in Vietnam. Summary of the Epidemiologic Literature Zober et al. (1990) noted that a squamous-cell carcinoma of the tonsil was among the 33 cancers diagnosed in 247 workers exposed during an accident at the BASF plant in Aktiengesellschaft 34 years earlier. Becher et al. (1996) conducted an occupational cohort study of 2,479 work- ers in four industrial plants in Germany, which did not include the factory reported on by Zober et al. (1990). The factories produced various herbicides, including those known to have been contaminated with TCDD. High dioxin and furan exposures have been documented by blood fat measurements in two of the four plants. In one of the factories where TCDD contamination was so docu- mented, one case of tonsil cancer was observed in a group of buccal-cavity and pharyngeal cancers (ICD-9 140–149), which as a group had a non-significantly increased SMR of 1.78. Rix et al. (1998) studied a cohort of 14,362 workers at Danish paper mills employed during 1943–1990. There were 17 cases of pharyngeal cancer (ICD-7 145–148) in the cohort: 15 in men (SIR 1.99, 95% CI 1.11–3.29) and 2 in women. The authors report that 11 of the 17 were in the tonsils, so the RR of tonsil cancers in particular would be about twice the corresponding RR for pharyngeal cancers as a whole. No new environmental or Vietnam-veteran studies concerning exposure to the compounds of interest and tonsil cancer were published since Update 2004. Synthesis Among all the cohort studies of populations potentially exposed to the compounds of interest reviewed by VAO committees, only Rix et al. (1998), Becher et al. (1996), and Zober et al. (1990) specifically stated an exact number of tonsil-cancer cases observed, as opposed to grouping them with the more general classification of oral, nasal, or pharyngeal cancers. The paucity of find- ings specifically related to tonsil cancer is a consequence of the extreme rarity of this type of cancer and its occurrence in an anatomic region whose cancers are generally grouped fairly idiosyncratically. That the tissue type developing into a neoplasm at this location might generate a carcinoma, a lymphoma, or a sarcoma has further constrained the committee’s ability to assemble a meaning-

CANCER 283 ful body of evidence addressing risk factors for this unusual type of cancer. A case–control protocol would probably be more effective in determining whether tonsil cancer is associated with exposure to the herbicides used in Vietnam, but we have been unable to locate any publications reporting studies of this design. Anecdotal reports from veterans to VA suggest that the tonsil might be responsive to their exposure experience in Vietnam, but the likelihood of evaluating such an association convincingly is small unless primary research is conducted to address it specifically. Conclusion The committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and tonsil cancer. CANCERS OF THE DIGESTIVE ORGANS Until this update, VAO committees have reviewed “gastrointestinal tract tu- mors” as a group consisting of stomach, colorectal, and pancreatic cancers, with esophageal cancer being formally factored in only by Update 2004. These can- cers are often subsumed under “cancers of the digestive organs,” a classification that traditionally includes “hepatobiliary cancers,” which have been considered separately by previous VAO committees. With evidence from occupational studies now available, this update and future updates will address cancers of the diges- tive organs individually. This section presents findings from reports since the last review that have considered cancers of the digestive organs as a group (ICD-9 150–159), which is in practice too broad for etiologic analyses; it then presents updated and integrated information on individual types of digestive cancer. Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 219,170 people would receive diagnoses of those cancers in the United States in 2006, and 112,670 people would die from them (Jemal et al., 2006). When other digestive cancers (for example, small intestine, anal, and hepatobiliary) were included, the 2006 estimates for the United States were about 263,060 new diagnoses and 136,180 deaths (Jemal et al., 2006). Collectively, tumors of the digestive organs were expected to account for 19 percent of new diagnoses and 24 percent of cancer deaths in 2006. The average annual incidences of gastrointestinal cancers are presented in Table 6-4. The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, incidence is higher in men than in women and higher in blacks than in whites. Other risk factors for the cancers vary but always include

284 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-4 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Stomach: Men 9.2 8.0 15.9 15. 6 14.0 20.9 25.6 22.8 42.5 Women 4.7 3.6 9.2 6.9 5.7 11.3 10.5 8.5 18.6 Esophagus: Men 9.5 9.5 13.7 16.6 16.2 30.1 23.8 23.9 33.0 Women 1.8 1.3 6.3 3.3 2.8 9.5 5.3 5.0 11.7 Colon (excluding the rectum): Men 35.3 33.7 52.1 59.7 57.5 88.8 99.9 96.3 154.6 Women 27.6 25.3 43.4 43.9 40.7 74.3 71.9 69.3 112.2 Rectum and Rectosigmoid Junction: Men 24.4 23.6 26.8 35.5 35.2 32.9 52.3 51.8 48.5 Women 14.7 13.8 18.9 22.1 21.7 29.7 28.1 27.8 35.9 Liver and Intrahepatic Bile Duct: Men 16.4 12.6 33.8 18.4 13.7 38.2 23.2 17.0 30.5 Women 2.9 2.2 4.9 4.7 3.6 9.2 7.9 5.6 8.9 Pancreas: Men 12.5 12.2 20.3 21.4 20.4 34.7 33.8 33.5 45.5 Women 7.8 7.4 11.4 13.8 13.0 18.1 23.7 22.5 37.6 Small Intestine: Men 3.1 3.0 5.1 5.0 4.7 10.6 5.3 5.2 5.5 Women 1.9 1.7 4.9 2.8 2.9 3.3 4.4 4.2 7.3 Anus, Anal Canal, and Anorectum: Men 2.1 2.0 4.1 2.3 2.5 2.1 3.4 3.5 5.0 Women 2.9 3.2 3.3 3.1 3.2 4.8 3.8 4.2 3.6 Other Digestive Organs: Men 0.6 0.4 0.7 0.8 0.9 0.7 1.1 1.1 1.5 Women 0.6 0.6 0.4 0.9 0.9 1.2 0.9 1.0 0.8 Gallbladder: Men 0.4 0.4 0.5 0.9 0.7 0.7 1.6 1.7 1.5 Women 1.2 1.1 1.6 1.8 1.8 0.9 3.2 3.2 2.8 Other Biliary: Men 1.2 1.0 1.9 2.6 2.5 3.5 4.0 4.0 2.5 Women 1.0 1.0 0.8 1.5 1.4 1.2 3.2 3.4 2.0 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003. family history of the same form of cancer, some diseases of the affected organ, and diet. Tobacco use is a risk factor for pancreatic cancer and possibly stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori in- creases the risk of stomach cancer. Type 2 diabetes is associated with an increased risk of cancers of the colon and pancreas (ACS, 2006).

CANCER 285 Conclusions from VAO and Updates The committee responsible for VAO concluded that there was limited or sug- gestive evidence of no association between exposure to the compounds of interest and gastrointestinal tract tumors (stomach, colon, rectal, and pancreatic tumors; esophageal tumors are included later). The evidence associated with hepatobili- ary cancers was judged inadequate to support an association with exposure to the compounds of interest. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change those conclusions. Update of the Epidemiologic Literature on All Cancers of the Digestive Organs Occupational Studies Since the last update, three occupational studies have reported data on all gastrointestinal and hepatic sites analyzed collectively. ’t Mannetje et al. (2005) completed a mortality study in New Zealand of 813 TCDD-exposed phenoxy her- bicide producers and 699 sprayers whose vital status was followed to 2000 from 1969 and 1973, respectively. Among producers and sprayers, rates of digestive cancers overall (including hepatic tumors, ICD-9 150–159) were not higher than expected (for producers: SMR 1.38, 95% CI 0.77–2.28; for sprayers: SMR 1.15, 95% CI 0.66–1.87). Reported results on specific tumor sites are discussed in subsections below. Alavanja et al. (2005) reported cancer incidence in a prospective cohort study of private pesticide applicators, commercial applicators, and spouses of farmer applicators followed for an average of 7.2 years. Cancer cases were identified through cancer registry files in North Carolina and Iowa. The incidence of diges- tive system cancers (including liver and gallbladder cancers) was significantly lower than expected in private applicators (SIR 0.83, 95% CI 0.76–0.91) and their spouses (SIR 0.85, 95% CI 0.72–0.99). The incidence in commercial ap- plicators was close to the expected (SIR 0.97, 95% CI 0.62–1.44). Blair et al. (2005a) reported cancer mortality in the same prospective cohort study of pesticide applicators and spouses in North Carolina and Iowa. After an average of only 5.3 years of follow-up, a reduction in the overall risk of digestive cancers was reported in the private applicators (SMR 0.7, 95% CI 0.6–0.8) and a more modest reduction in their spouses (SMR 0.9, 95% CI 0.7–1.2). Environmental Studies No new environmental studies concerning exposure to the compounds of interest and digestive system cancers were published since Update 2004.

286 VETERANS AND AGENT ORANGE: UPDATE 2006 Vietnam-Veteran Studies In a set of three reports updating the health status of Australian Vietnam veterans, results concerning possible associations between Vietnam service and gastrointestinal cancers were reported; colorectal and stomach cancers were combined, and hepatobiliary cancers were reported separately. The SIR for gas- trointestinal cancers was 1.05 (95% CI 0.97–1.12) when veterans were compared with the general population of Australia (ADVA, 2005a). Mortality from gastroin- testinal cancers was unaffected (SMR 0.96, 95% CI 0.86–1.06) when veterans were compared with the general population (ADVA, 2005b). A separate report compared the rates of gastrointestinal cancer in deployed and non-deployed National Service Vietnam veterans (ADVA, 2005c); the increase in incidence in the deployed did not reach significance (RR 1.06, 95% CI 0.82–1.36), and the RR of death from gastrointestinal cancer was not increased (RR 0.81, 95% CI 0.52–1.24). Pavuk et al. (2005) analyzed the cancer incidence in 1,482 US Air Force veterans who were referent controls for the Ranch Hand subjects in the Air Force Health Study. The veterans had served in Southeast Asia, primarily conducting transport missions while stationed in Taiwan, the Philippines, Guam, Japan, or Thailand. The 24 cases of digestive system cancer (not explicitly defined) yielded an RR of 1.8 (95% CI 0.8–3.9) on the basis of serum TCDD concentrations (the natural logarithm was used in a Cox model). The highest quartile of TCDD (5.2–54.8 pg/g of lipid) was associated with an RR of digestive system cancer of 3.3 (95% CI 0.9–12.5). In contrast, on the basis of the number of years served in Southeast Asia, the overall RR of digestive system cancer was somewhat more convincingly increased (RR 1.2, 95% CI 1.0–1.4), but the highest quartile for this measure of exposure (3.7–16.4 years) was associated with an RR of 2.1 (95% CI 0.6–7.3). In analyses of Ranch Hand subjects themselves (Akhtar et al., 2004) discussed in Update 2004, there was no suggestion of an association between herbicide exposure in Vietnam and digestive system cancers. Esophageal Cancer Epithelial tumors of the esophagus (squamous-cell carcinomas and adeno- carcinomas) are responsible for more than 95 percent of all esophageal cancers (ICD-9 150); 14,550 newly diagnosed cases and 13,770 deaths were estimated for 2006 (Jemal et al., 2006). The considerable geographic variation in the incidence of esophageal tumors suggests that multifactorial etiology is responsible. Rates of esophageal cancer have been increasing in the last 2 decades. Adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most com- mon type of esophageal malignancy in the United States and western Europe (Blot and McLaughlin, 1999). Squamous-cell esophageal carcinoma is seen more commonly in blacks than in whites and in men than in women. Smoking

CANCER 287 and alcohol ingestion are also associated with the development of squamous- cell carcinoma. Smoking and alcohol are less well linked to the development of esophageal adenocarcinoma. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease, and the rise in chronic inflammation has been linked to the observed increase in esophageal adenocarcinoma. Conclusions from VAO and Updates This update considers esophageal cancer independently for the first time. Prior updates developed a table of results for esophageal cancer, but conclusions about the adequacy of the evidence of its association with herbicide exposure were reached in the context of gastrointestinal tract cancers. Table 6-5 summa- rizes the results of the relevant studies concerning esophageal cancer. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. A JEM was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine compounds (which would include TCDD). Death from esophageal cancer was not more strongly associated with having ever been exposed to nonvolatile organo- chlorine compounds (n 26; SMR 0.78, 95% CI 0.51–1.15) than with having never been exposed (n 27; SMR 0.71, 95% CI 0.41–1.03). In the mortality study of phenoxy herbicide producers and sprayers in New Zealand (’t Mannetje et al., 2005), the numbers of observed and expected deaths from esophageal cancer were so small that the estimated risks in the producer group (SMR 1.94, 95% CI 0.24–7.02) and in the sprayer group (SMR 0.72, 95% CI 0.0–3.99) were in effect indeterminate. In their study of cancer incidence in private and commercial pesticide ap- plicators and in the spouses of the private applicators in the AHS, Alavanja et al. (2005) did not report results separately for esophageal cancer. Reporting on cancer mortality in the same prospective cohort study, Blair et al. (2005a) found death from esophageal cancer to be less frequent than expected in the private applicators (SMR 0.5, 95% CI 0.3–0.9); only one case was observed in their spouses. Lee et al. (2004a) conducted a population-based case–control study of 170 cases of adenocarcinoma of the stomach and 137 cases of adenocarcinoma of the esophagus during 1988–1993. Controls were randomly selected from the same geographic area. Living on a farm, duration of farming, and having ever used herbicides were not associated with an increased risk of either type of cancer. No indication of increased risk of esophageal cancer was observed in connection with self-reported use of phenoxy herbicides, 2,4,5-T, or 2,4-D.

288 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-5 Selected Epidemiologic Studies—Esophageal Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 27 0.7 (0.4–1.0) Ever 26 0.8 (0.5–1.2) Blair et al., US Agriculture Health Study 2005a Private applicators (men and women) 16 0.5 (0.3–0.9) Spouses of private applicators ( 99% women) 1 0.3 (0.1–1.9) ’t Mannetje Phenoxy herbicide producers (men and women) 2 2.0 (0.2–7.0) et al., 2005 Phenoxy herbicide sprayers ( 99% men) 1 0.7 (0.0–4.0) Lee et al., Population-based case–control—agricultural pesticide 2004a use and adenocarcinoma of the esophagus 137 Insecticides 0.7 (0.4–1.1) Herbicides 0.7 (0.4–1.2) Reif et al., New Zealand forestry workers—nested case–control 1989 (incidence) correspondence 4 1.8 (0.7–4.8) Magnani UK case–control et al., 1987 Herbicides * 1.6 (0.7–3.6) Chlorophenols * 1.2 (0.7–2.2) Studies Reviewed in Update 1998 Kogevinas IARC cohort (men and women) et al., 1997 Workers exposed to any phenoxy herbicide or chlorophenol 28 1.0 (0.7–1.4) Exposed to TCDD (or higher-chlorinated dioxins) 20 1.3 (0.8–1.9) Not exposed to TCDD (or higher-chlorinated dioxins) 6 0.5 (0.2–1.1) Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators—incidence 3 1.6 (0.3–4.6) 1994 Finnish herbicide applicators—mortality 2 1.3 (0.2–4.7) Studies Reviewed in VAO Ronco et al., Danish farm workers—incidence 1992 Men—Self-employed 32 0.4 (p 0.05) Employee 13 0.9 (*) Women—Self-employed 1 1.4 (*) Family worker 2 0.4 (*) Saracci et al., IARC cohort—exposed subcohort (men and women) 8 0.6 (0.3–1.2) 1991 Coggon British MCPA production workers (included in the et al., 1986 IARC cohort) 8 0.9 (0.4–1.9) Wiklund, Swedish men and women agricultural 1983 workers—incidence 169 0.6 (0.5–0.7)

CANCER 289 TABLE 6-5 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c ENVIRONMENTAL None VIETNAM VETERANS New Studies ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 70 1.2 (0.9–1.5) Navy 19 1.6 (0.9–2.4) Army 40 1.1 (0.7–1.4) Air Force 11 1.5 (0.8–2.8) ADVA, Australian male Vietnam veterans vs Australian 2005b population—Mortality 67 1.1 (0.8–1.3) Navy 13 1.0 (0.5–1.7) Army 42 1.0 (0.7–1.3) Air Force 12 1.5 (0.8–2.6) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs non-deployed Incidence 9 1.9 (0.6–6.6) Mortality 10 1.3 (0.5–3.6) Boehmer Follow-up of CDC Vietnam Experience Cohort 6 1.2 (0.4–4.0) et al., 2004 Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 23 1.2 (0.7–1.7) CDVA, 1997b Australian national service Vietnam veterans 1 1.3 (0.0– 10) ABBREVIATIONS: ADVA, Australian Department of Veteran Affairs; CDVA, Commonwealth De- partment of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Edition; MCPA, methyl-4-chloro- phenoxyacetic acid. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. Studies in italics have been superseded by newer studies of the same cohort. Starting with the 19,904 men entered into the the New Zealand Cancer Reg- istry from 1980–1984 with a specified occupation, Reif et al. (1989) contrasted the 385 cases of esophageal cancer with the remaining subjects having other types of cancer. Of the 134 cancer registrants for whom forestry worker (with presumed exposure to phenoxyherbicides and chlorophenols) was the most recent occupation, the proportion with esophageal cancer (4 cases; OR 1.77, 95% CI 0.66–4.75) was not significantly elevated.

290 VETERANS AND AGENT ORANGE: UPDATE 2006 Magnani et al. (1987) reported a case–control mortality study of 244 cases of esophageal cancer and 935 controls in the UK. A JEM was used to predict ex- posures to various chemical agents on the basis of job title as indicated on death certificates. Estimates of risk of esophageal cancer associated with exposure to herbicides (RR 1.6, 95% CI 0.7–3.6) and chlorophenols (RR 1.2, 95% CI 0.7–2.2) were not significantly increased. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and esophageal cancer were published since Update 2004. Vietnam-Veteran Studies In reports updating the health status of Australian Vietnam veterans, 70 cases of esophageal cancer were diagnosed (SIR 1.22, 95% CI 0.94–1.51) (ADVA, 2005a), and there were 67 deaths from esophageal cancer (SMR 1.06, 95% CI 0.81–1.32) (ADVA, 2005b). In a separate study of diagnoses and deaths in deployed and non-deployed National Service veterans, the trend toward an increased rate of esophageal cancer remained with an RR of 1.93 (95% CI 0.61–6.59) for incidence and an RR of 1.33 (95% CI 0.50–3.55) for mortality based on nine observed cases (ADVA, 2005c). In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported six esophageal-cancer deaths in the deployed and five in the non- deployed (crude rate ratio [CRR], 1.2, 95% CI 0.4–4.0). Biologic Plausibility The committee did not find any new studies that supported the biologic plau- sibility of an association of exposure to the compounds of interest and esophageal cancer. The biologic plausibility of the carcinogenicity of the compounds of inter- est in general is summarized at the end of this chapter. Synthesis Previous updates did not review the risk of esophageal cancer separately. Reviewing the epidemiologic studies of esophageal cancer to date yielded no evidence of an increased risk associated with the compounds of interest. The recent updates of the health status of the Australian Vietnam veterans present an interesting but non-significant pattern of increased risk of esophageal cancer. No toxicologic studies provide evidence of biologic plausibility of an association between the compounds of interest and tumors of the esophagus. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient

CANCER 291 evidence to determine whether there is an association between exposure to the compounds of interest and esophageal cancer. Stomach Cancer The incidence of stomach cancer (ICD-9 151) increases in people 50–64 years old. ACS estimated that in 2006 13,400 men and 8,880 women would develop new cases of stomach cancer and 6,690 men and 4,740 women would die from it (Jemal et al., 2006). In general, the incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history of this cancer, some diseases of the stomach, and diet. Infection with the bacterium Helicobacter pylori increases the risk of stomach cancer. Tobacco use, consumption of salt-preserved food, and a high salt intake may also increase the risk of stomach cancer (Key et al., 2004; Miller et al., 1996). Conclusions from VAO and Updates This update considers stomach cancer independently for the first time. Prior updates developed a table of results for stomach cancer, but conclusions about the adequacy of the evidence of its association with herbicide exposure have been reached in the context of gastrointestinal tract cancers. Table 6-6 summarizes the results of the relevant studies concerning stomach cancer. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. A JEM was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine com- pounds (which would include TCDD). Death from stomach cancer was not more strongly associated with having ever been exposed to nonvolatile organochlorine compounds (n 98; SMR 0.89, 95% CI 0.72–1.08) than with having never been exposed (n 146; SMR 0.93, 95% CI 0.79–1.10). In the mortality study of phenoxy herbicide producers and sprayers in New Zealand (’t Mannetje et al., 2005), the numbers of observed and expected deaths from stomach cancer among producers (n 2) and sprayers (n 3) were so small that the estimated risks were in effect indeterminate. In their study of cancer incidence in private and commercial pesticide ap- plicators and the spouses of the private applicators in the AHS, Alavanja et al. (2005) did not report results separately for stomach cancer. Reporting on cancer mortality in the same prospective cohort study, Blair et al. (2005a) found death from stomach cancer to be reduced in the private applicators (SMR 0.5, 95% CI 0.2–1.0) and as expected in their spouses (SMR 1.1, 95% CI 0.3–2.8). Lee et al. (2004a) conducted a population-based case–control study of 170 cases of adenocarcinoma of the stomach and 137 cases of adenocarcinoma of the esophagus in 1988–1993. Controls were randomly selected from the same

292 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-6 Selected Epidemiologic Studies—Stomach Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 146 0.9 (0.8–1.1) Ever 98 0.9 (0.7–1.1) Alavanja et al., 2005 US Agriculture Health Study—incidence Private applicators (men and women) 462 0.8 (0.8–0.9) Spouses of private applicators ( 99% women) 161 0.9 (0.7–1.0) Commercial applicators (men and women) 24 1.0 (0.6–1.4) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) 10 0.5 (0.2–1.0) Spouses of private applicators ( 99% women) 4 1.1 (0.3–2.8) ’t Mannetje et al., Phenoxy herbicide producers (men and 2005 women) 2 1.1 (0.1–4.0) Phenoxy herbicide sprayers ( 99% men) 3 1.4 (0.3–4.0) Lee et al., 2004a Population-based case–control— agricultural pesticide use and adenocarcinoma of the stomach 170 Insecticides 0.9 (0.6–1.4) Herbicides 0.9 (0.5–1.4) Torchio et al., 1994 Italian licensed pesticide users 126 0.7 (0.6–0.9) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 13 2.2 (1.3–3.9) Studies Reviewed in Update 2004 Bodner et al., 2003 Dow production workers (included in the IARC cohort and the NIOSH Dioxin Registry) — 1.5 (0.7–2.7) Swaen et al., 2004 Dutch licensed herbicide applicators 3 0.4 (0.1–1.3)d Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) Digestive organs and peritoneum 16 0.7 (0.4–1.2) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 13 1.0 (0.6–1.8) Hooiveld et al., 1998 Dutch chemical production workers (included in the IARC cohort) 3 1.0 (0.2–2.9)

CANCER 293 TABLE 6-6 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Rix et al., 1998 Danish paper mill workers—incidence Men 48 1.1 (0.8–1.4) Women 7 1.0 (0.4–2.1) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 39 1.0 (0.7–1.3) Kogevinas et al., 1997 IARC cohort (men and women) Workers exposed to any phenoxy herbicide or chlorophenol 72 0.9 (0.7–1.1) Workers exposed to TCDD (or higher-chlorinated dioxins) 42 0.9 (0.7–1.2) Workers not exposed to TCDD (or higher-chlorinated dioxins) 30 0.9 (0.6–1.3) Becher et al., 1996 German production workers (included in the IARC cohort) Plant I 12 1.3 (0.7–2.2) Plant II 0 — Plant III 0 — Plant IV 2 0.6 (0.1–2.3) Ott and Zober, 1996 BASF employees—incidence 3 1.0 (0.2–2.9) TCDD g/kg of body weight 0.1 0 0.0 (0.0–3.4) 0.1–0.99 1 1.3 (0.0–7.0) 1t 2 1.7 (0.2–6.2) Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 4 1.7 (0.5–4.3) 15-year latency 3 1.8 (0.4–5.2) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 657 1.0 (1.0–1.1) White women 12 1.2 (0.6–2.0) Bueno de Mesquita Dutch phenoxy herbicide workers et al., 1993 (Included in the IARC cohort) 2 0.7 (0.1–2.7) Collins et al., 1993 Monsanto Company workers (included in NIOSH cohort) 0 0.0 (0.0–1.1) Kogevinas et al., 1993 IARC cohort—women 1 1.4* Studies Reviewed in VAO Ronco et al., 1992 Danish farm workers—incidence Men 286 0.9* Women 5 1.0* Swaen et al., 1992 Dutch licensed herbicide applicators 1 0.5 (0.0–2.7)d Fingerhut et al., 1991 NIOSH—entire cohort 10 1.0 (0.5–1.9) 1-year exposure; 20-year latency 4 1.4 (0.4–3.5) continued

294 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-6 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Manz et al., 1991 German production workers—men and women (included in the IARC cohort) Men 12 1.2 (0.6–2.1) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 40 0.9 (0.6–1.2) Wigle et al., 1990 Canadian farmers 246 0.9 (0.8–1.0) Zober et al., 1990 BASF employees—basic cohort 3 3.0 (0.8–7.7)e Alavanja et al., 1989 USDA forest or soil conservationists 9 0.7 (0.3–1.3) Henneberger et al., New Hampshire pulp and paper 1989 workers 5 1.2 (0.4–2.8) Solet et al., 1989 US paper and pulp workers 1 0.5 (0.1–3.0) Alavanja et al., 1988 USDA agricultural extension agents 10 0.7 (0.4–1.4) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0 — (0.0–3.7) Thomas, 1987 US flavor and fragrance chemical plant workers 6 4.2 Expected Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) 26 0.9 (0.6–1.3) Robinson et al., 1986 Northwestern US paper and pulp workers 17 1.2 (0.8–1.9)e Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 12 1.3* Women 1 0.7* Blair et al., 1983 Florida pesticide applicators 4 3.3 Expected Burmeister et al., 1983 Iowa residents—farming exposures 1,812 1.3 (p 0.05) Wiklund, 1983 Swedish male and female agricultural workers—incidence 2,599 1.1 (1.0–1.2)f Burmeister, 1981 Iowa farmers 338 1.1 (p 0.01) Axelson et al., 1980 Swedish railroad workers—total exposure 3 2.2* ENVIRONMENTAL Studies Reviewed in Update 2004 Fukuda et al., 2003 Residents of municipalities in Japan with or without waste incineration plants Age-adjusted mortality (100,000) 38.2 7.8 vs in men 39.0 8.8 (p 0.29) Age-adjusted mortality (100,000) in 20.7 5.0 vs women 20.7 5.8 (p 0.92) Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Men 59 1.7 (1.3–2.2) Women 45 0.7 (0.5–0.9)

CANCER 295 TABLE 6-6 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Zones A, B—men 16 0.9 (0.5–1.5) women 11 1.0 (0.6–1.9) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone A—women 1 0.9 (0.0–5.3) Zone B—men 10 0.8 (0.4–1.5) women 7 1.0 (0.4–2.1) Zone R—men 76 0.9 (0.7–1.1) women 58 1.0 (0.8–1.3) Svensson et al., 1995 Swedish fishermen—mortality (men and women) East coast 17 1.4 (0.8–2.2) West coast 63 0.9 (0.7–1.2) Swedish fishermen—incidence (men and women) East coast 24 1.6 (1.0–2.4) West coast 71 0.9 (0.7–1.2) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—incidence Zone B—men 7 1.0 (0.5–2.1) women 2 0.6 (0.2–2.5) Zone R—men 45 0.9 (0.7–1.2) women 25 1.0 (0.6–1.5) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents—incidence Zones A, B—men 7 0.9 (0.4–1.8) women 3 0.8 (0.3–2.5) Bertazzi et al., 1989a Seveso residents—10-year follow-up Zones A, B, R—men 40 0.8 (0.6–1.2) women 22 1.0 (0.6–1.5) Bertazzi et al., 1989b Seveso residents—10-year follow-up Zone B—men 7 1.2 (0.6–2.6) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 104 0.9 (0.7–1.1) Navy 28 1.1 (0.7–1.6) Army 66 0.9 (0.7–1.1) Air Force 10 0.7 (0.3–1.3) continued

296 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-6 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 76 0.9 (0.7–1.2) Navy 22 1.3 (0.8–1.8) Army 50 0.9 (0.7–1.2) Air Force 4 0.4 (0.1–1.0) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 11 0.6 (0.2–1.2) Mortality 7 0.7 (0.2–2.0) Pavuk et al., 2005 White Air Force comparison subjects only (digestive system)—incidence Serum TCDD levels (pg/g), based on model with exposure variable loge(TCDD)f Per unit increase of -loge(TCDD) in pg/g 24 1.8 (0.8–3.9) Quartiles (pg/g) 0.4–2.6 4 —* 2.6–3.8 3 1 (0.2–4.8) 3.8–5.2 7 2 (0.5–8.2) 5.2 10 3.3 (0.9–12.5) Number of years served in Southeast Asia (SEA) Per year of service 24 1.2 (1–1.4) Quartiles (years in SEA) 0.8–1.3 4 1.3–2.1 4 1 (0.2–3.8) 2.1–3.7 5 1.1 (0.3–4.2) 3.7–16.4 11 2.1 (0.6–7.3) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort (stomach) 5 —* Studies Reviewed in Update 2004 Akhtar et al., 2004 Air Force Ranch Hand veterans— cancer of the digestive system All Ranch Hand veterans Incidence (SIR) 16 0.6 (0.4–1.0) Mortality (SMR) 6 0.4 (0.2–0.9) Veterans, tours 1966–1970—incidence 14 0.6 (0.4–1.1) White Air Force comparison veterans— cancer of the digestive system All comparison veterans Incidence (SIR) 31 0.9 (0.6–1.2) Mortality (SMR) 14 0.7 (0.4–1.1) Veterans, tours 1966–1970—incidence 24 0.9 (0.6–1.3)

CANCER 297 TABLE 6-6 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 32 1.1 (0.7–1.4) CDVA, 1997b Australian national service Vietnam veterans 4 1.7 (0.3– 10) Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 88 1.1 (0.9–1.5) Marine Vietnam veterans 17 0.8 (0.4–1.6) Anderson et al., 1986b Wisconsin Vietnam veterans 1 —* ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ADVA, Australian Department of Vet- eran Affairs; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; MCPA, 2 methyl-4-chlorophenoxyacetic acid; TCDD, 2,3,7,8-tetrachlo- rodibenzo-p-dioxin; USDA, US Department of Agriculture. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d Risk estimate is for stomach and small intestine. e 90% CI f 99% CI. g Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort. geographic area. Living on a farm, duration of farming, and having ever used herbicides were not associated with an increased risk of either type of cancer. No indication of an increased risk of stomach cancer was observed in association with self-reported use of phenoxy herbicides (OR 0.8, 95% CI 0.5–1.5), 2,4,5-T (OR 0.7, 95% CI 0.3–1.7), or 2,4-D (OR 0.8, 95% CI 0.4–1.3). Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re- ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of dying from stomach cancer was significantly reduced among the licensed pesticide users (126 cases; SMR 0.72, 95% CI 0.6–0.86) when compared with regional and provincial populations. The authors suggested that the relatively short duration of follow-up and the healthy-worker effect contributed to the ob- servation of a reduction in mortality. Starting with the 19,904 men entered into the the New Zealand Cancer Reg- istry from 1980–1984 with a specified occupation, Reif et al. (1989) contrasted the 1,014 cases of stomach cancer with the remaining subjects having other types of cancer. Of the 134 cancer registrants for whom forestry worker (with

298 VETERANS AND AGENT ORANGE: UPDATE 2006 presumed exposure to phenoxyherbicides and chlorophenols) was the most recent occupation, the proportion with stomach cancer (13 cases; OR 2.22, 95% CI 1.26–3.91) was significantly elevated. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and stomach cancer were published since Update 2004. Vietnam-Veteran Studies In the three reports updating the health status of Australian Vietnam veterans, 104 diagnoses of stomach cancer (SIR 0.89, 95% CI 0.72–1.07) and 76 deaths (SMR 0.94, 95% CI 0.73–1.15) were reported (ADVA, 2005a,b). No increase was reported in the National Service veteran study that examined the healthy-warrior effect (ADVA, 2005b). In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported five stomach-cancer deaths in the deployed and three in the non- deployed. The researchers did not consider the data sufficient for the calculation of risk statistics unless there were at least 10 deaths from a type of cancer. Biologic Plausibility No animal studies have reported an increased incidence of gastrointestinal cancer after exposure to the compounds of interest. However, treatment with TCDD in some animal models (female hairless mice) has been reported to result in hyperplasia of mucous cells in the fundic region of the stomach (Hebert et al., 1990). In addition, a transgenic mouse bearing a constitutively active form of the aryl hydrocarbon receptor (AhR) has been shown to develop stomach tumors (Andersson et al., 2002a). The tumors are neither dysplastic nor metaplastic but are indicative of both squamous and intestinal type metaplasia (Andersson et al., 2005). The validity of the transgenic animal model is indicated by the similarities in the phenotype of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of the AhR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006). The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis The risk of stomach cancers has not been reviewed separately in previous updates. Among the newly reviewed studies, only Reif et al. (1989) reported a significant relationship, which was between stomach cancer and the rather non- specific exposure of being a forestry worker. There is some evidence of biologic plausibility in animal models, but the epidemiologic studies to date do not sup- port an association between exposure to the compounds of interest and stomach cancer.

CANCER 299 Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and stomach cancer. Colorectal Cancer Colorectal cancers include malignancies of the colon (ICD-9 153) and of the rectum and anus (ICD-9 154); less prevalent tumors of the small intestine (ICD- 9 152) are frequently included in this grouping. Should any findings on cancers of the retroperitoneum and other and unspecified digestive organs (ICD-9 159) be found, they will be considered in this category. Colorectal cancers account for about 55 percent of digestive tumors; ACS estimated that in 2006 148,610 people would develop new cases and 55,170 would die from the cancers in the United States (ACS, 2006). Excluding basal-cell and squamous-cell skin cancers, colorectal cancer is the third-most common form of cancer both in men and in women. The incidence of colorectal cancer increases with age; it is higher in men than in women and in blacks than in whites. Because it is recommended that all persons over 50 years old receive colon-cancer screening, screening can affect incidence rates. Other risk factors include family history of this form of cancer, some diseases of the intestines, and diet. Type 2 diabetes is associated with an increased risk of cancer of the colon (ACS, 2007a). Conclusions from VAO and Updates This update considers colorectal cancer independently for the first time. Prior updates developed tables of results for colon and rectal cancer, but conclusions about the adequacy of the evidence of their association with herbicide exposure have been reached only in the context of gastrointestinal tract cancers. Tables 6-7 and 6-8 summarize the results of the relevant studies concerning colon and rectal cancers, respectively. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. A JEM was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine com- pounds (which would include TCDD). Death from colon cancer was significantly decreased among those who had been exposed to nonvolatile organochlorine com- pounds (n 62; SMR 0.74, 95% CI 0.57–0.95) but not among those who had never been exposed (n 106; SMR 1.04, 95% CI 0.85–1.25). Death from rectal

300 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-7 Selected Epidemiologic Studies—Colon Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 106 1.0 (0.9–1.3) Ever 62 0.7 (0.6–1.0) Alavanja et al., 2005 US Agriculture Health Study—incidence Private applicators (men and women) 208 0.9 (0.8–1.0) Spouses of private applicators ( 99% women) 12 1.2 (0.6–2.1) Commercial applicators (men and women) 87 0.9 (0.7–1.1) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) 56 0.7 (0.6–1.0) Spouses of private applicators ( 99% women) 31 1.2 (0.8–1.6) ’t Mannetje et al., 2005 Phenoxy herbicide producers (men and women) 2 0.6 (0.0–2.3) Phenoxy herbicide sprayers ( 99% men) 8 1.9 (0.8–3.8) Torchio et al., 1994 Italian licensed pesticide users Large intestine 84 0.6 (0.5–0.7) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 7 0.5 (0.2–1.1) Small intestine 2 5.2 (1.4–18.9) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 34 1.2 (0.8–1.6)d Hooiveld et al., 1998 Dutch chemical production workers (included in the IARC cohort) 3 1.4 (0.3–4.0) Rix et al., 1998 Danish paper mill workers—incidence Men 58 1.0 (0.7–1.2) Women 23 1.1 (0.7–1.7) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 27 1.1 (0.7–1.6) Kogevinas et al., 1997 IARC cohort (men and women) Workers exposed to any phenoxy herbicide or chlorophenol 86 1.1 (0.9–1.3) Exposed to TCDD (or higher- chlorinated dioxins) 52 1.0 (0.8–1.3) Not exposed to TCDD (or higher- chlorinated dioxins) 33 1.2 (0.8–1.6)

CANCER 301 TABLE 6-7 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Becher et al., 1996 German production workers (included in the IARC cohort) Plant I 2 0.4 (0.1–1.4) Plant II 0 — Plant III 1 2.2 (0.1–12.2) Plant IV 0 — Ott and Zober, 1996e BASF employees—incidence 5 1.0 (0.3–2.3) TCDD g/kg of body weight) 0.1 2 1.1 (0.1–3.9) 0.1–0.99 2 1.4 (0.2–5.1) 1 1 0.5 (0.0–3.0) Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 4 0.8 (0.2–2.1) 15-year latency 4 1.0 (0.3–2.6) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 2,291 1.0 (0.9–1.0) White women 59 1.0 (0.8–1.3) Bueno de Mesquita Dutch phenoxy herbicide workers (included et al., 1993 in the IARC cohort) 3 1.8 (0.4–5.4) Collins et al., 1993 Monsanto Company workers (included in the NIOSH cohort) 3 0.5 (0.1–1.3) Studies Reviewed in VAO Swaen et al., 1992 Dutch licensed herbicide applicators 4 2.6 (0.7–6.5) Ronco et al., 1992 Danish workers—incidence Men—self-employed 277 0.7 (p 0.05) employee 45 0.6 (p 0.05) Women—self-employed 14 0.9 (*) employee 112 0.9 (*) family worker 2 0.2 (p 0.05) Fingerhut et al., 1991 NIOSH—entire cohort 25 1.2 (0.8–1.8)d 1-year exposure; 20-year latency 13 1.8 (1.0–3.0)d Manz et al., 1991 German production workers (included in the IARC cohort) 8 0.9 (0.4–1.8) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 41 1.1 (0.8–1.5) Zober et al., 1990b.e BASF employees—basic cohort 2 2.5 (0.4–7.8)f Alavanja et al., 1989 USDA forest or soil conservationists 44g 1.5 (1.1–2.0) Henneberger et al., 1989 New Hampshire pulp and paper workers 9 1.0 (0.5–2.0) Solet et al., 1989 US pulp and paper workers 7 1.5 (0.6–3.0) Alavanja et al., 1988 USDA agricultural extension agents 41 1.0 (0.7–1.5) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 4 2.1 (0.6–5.4) continued

302 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-7 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Thomas, 1987 US flavor and fragrance chemical plant workers 4 0.6* Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) 19 1.0 (0.6–1.6) Robinson et al., 1986 Northwestern US pulp and paper workers 7 0.4 (0.2–0.7)f Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 10 1.0* Women 1 0.3* Blair et al., 1983 Florida pesticide applicators 5 0.8* Wiklund, 1983 Swedish male and female agricultural workers—incidence 1,332 0.8 (0.7–0.8)h Thiess et al., 1982 BASF production workers 1 0.4* Burmeister, 1981 Iowa farmers 1,064 1.0 (NS) Hardell, 1981 Swedish residents Exposed to phenoxy acids 11 1.3 (0.6–2.8) Exposed to chlorophenols 6 1.8 (0.6–5.3) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Men 17 1.3 (0.8–2.2) Women 24 1.0 (0.7–1.5) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Zones A, B—men 10 1.0 (0.5–1.9) women 5 0.6 (0.2–1.4) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone A—women 2 2.6 (0.3–9.4) Zone B—men 5 0.8 (0.3–2.0) women 3 0.6 (0.1–1.8) Zone R—men 34 0.8 (0.6–1.1) women 33 0.8 (0.6–1.1) Svensson et al., 1995 Swedish fishermen—mortality (men and women) East coast 1 0.1 (0.0–0.7) West coast 58 1.0 (0.8–1.3) Swedish fishermen—incidence (men and women) East coast 5 0.4 (0.1–0.9) West coast 82 1.0 (0.8–1.2)

CANCER 303 TABLE 6-7 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—morbidity Zone B—men 2 0.5 (0.1–2.0) women 2 0.6 (0.1–2.3) Zone R—men 32 1.1 (0.8–1.6) women 23 0.8 (0.5–1.3) Studies Reviewed in VAO Lampi et al., 1992 Finnish community exposed to chlorophenol contamination (men and women) 9 1.1 (0.7–1.8) Pesatori et al., 1992 Seveso residents—incidence Zones A, B—men 3 0.6 (0.2–1.9) women 3 0.7 (0.2–2.2) Bertazzi et al., 1989a Seveso residents—10-year follow-up Zones A, B, R—men 20 1.0 (0.6–1.5) women 12 0.7 (0.4–1.2) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 376 1.1 (1.0–1.2) Navy 91 1.3 (1.0–1.5) Army 239 1.1 (0.9–1.2) Air Force 47 1.1 (0.8–1.5) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 176 1.0 (0.8–1.1) Navy 49 1.3 (0.9–1.6) Army 107 0.9 (0.7–1.0) Air Force 21 0.9 (0.5–1.3) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 54 0.9 (0.7–1.4) Mortality 29 0.8 (0.5–1.3) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort (colon, rectum, anus) 9 1.0 (0.4–2.6) Studies Reviewed in Update 2000 AFHS, 2000e Air Force Ranch Hand veterans 7 1.5 (0.4–5.5) AIHW, 1999e Australian Vietnam veterans—men 188 221 expected (191–251) CDVA, 1998a Australian Vietnam veterans—men 405j 117 expected (96–138) CDVA, 1998b Australian Vietnam veterans—women 1j 1 expected (0–5) continued

304 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-7 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 78 1.2 (0.9–1.5) CDVA, 1997b Australian National Service Vietnam 6 0.6 (0.2–1.5) veterans Studies Reviewed in Update 1996 Dalager et al., 1995 US Vietnam veterans—women 4 0.4 (0.1–1.2) Vietnam veteran nurses 4 0.5 (0.2–1.7) Studies Reviewed in VAO Breslin et al., 1988k Army Vietnam veterans 209 1.0 (0.7–1.3) Marine Vietnam veterans 33 1.3 (0.7–2.2) Anderson et al., 1986b Wisconsin Vietnam veterans 6 1.0 (0.4–2.2) 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, methyl-4- 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. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d Colon and small intestine combined. e Colon and rectal cancer results combined. f 90% CI. g p 0.01. h 99% CI. i Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity. j Self-reported medical history. Answer to question: “Since your first day of service in Vietnam, have you been told by a doctor that you have cancer of the colon?” k Intestinal and other GI cancer results are combined in this study. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort. cancer, however, was not more strongly associated with having ever been exposed to nonvolatile organochlorine compounds (n 51; SMR 0.96, 95% CI 0.71–1.26) than with having never been exposed (n 60; SMR 0.87, 95% CI 0.66–1.12). In their prospective cohort study of cancer incidence in private commercial pesticide applicators, Alavanja et al. (2005) found the incidence of rectal cancer significantly lower than expected (SIR 0.81, 95% CI 0.65–0.99) and the inci- dence of colon cancer similar to that predicted in the general population (SIR 0.88, 95% CI 0.76–1.01). In commercial applicators, the incidence of colon

CANCER 305 TABLE 6-8 Selected Epidemiologic Studies—Rectal Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 60 0.9 (0.7–1.1) Ever 51 1.0 (0.7–1.3) Alavanja et al., 2005 US Agriculture Health Study—incidence Private applicators (men and women) 94 0.8 (0.7–1.0) Spouses of private applicators ( 99% women) 23 0.6 (0.4–0.9) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) * * Spouses of private applicators ( 99% women) * * ’t Mannetje et al., Phenoxy herbicide producers (men and women) 5 2.5 (0.8–5.7) 2005 Phenoxy herbicide sprayers ( 99% men) 4 1.5 (0.4–3.8) Torchio et al., 1994 Italian licensed pesticide users * * Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 10 1.2 (0.6–2.3) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators 5 2.1 (0.7–4.8) Studies Reviewed in Update 2000 Steenland et al., US chemical production workers (included 1999 in the IARC cohort and the NIOSH Dioxin Registry) 6 0.9 (0.3–1.9) Hooiveld et al., Dutch chemical production workers (included in 1998 the IARC Cohort) 1 1.0 (0.0–5.6) Rix et al., 1998 Danish paper mill workers—incidence Men 43 0.9 (0.6–1.2) Women 15 1.5 (0.8–2.4) Studies Reviewed in Update 1998 Kogevinas et al., IARC cohort (men and women) 1997 Workers exposed to any phenoxy herbicide or chlorophenol 44 1.1 (0.8–1.4) Exposed to TCDD (or higher-chlorinated dioxins) 29 1.3 (0.9–1.9) Not exposed to TCDD (or higher- chlorinated dioxins) 14 0.7 (0.4–1.2) Becher et al., 1996 German production workers (included in the IARC Cohort) Plant I 6 1.9 (0.7–4.0) Plant II 0 — Plant III 0 — Plant IV 1 0.9 (0.0–4.9) continued

306 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-8 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 0 — 15-year latency 0 — Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 367 1.0 (0.9–1.1) White women 4 0.5 (0.1–1.3) Bueno de Mesquita Dutch phenoxy herbicide workers (included in et al., 1993 the IARC cohort) 0 0 (0.0–4.3) Studies Reviewed in VAO Ronco et al., 1992 Danish workers—incidence Men—self-employed 309 0.8 (p 0.05) employee 55 0.8 (*) Women—self-employed 5 0.6 (*) employee 55 0.8 (*) family worker 2 0.4 (*) Fingerhut et al., NIOSH—entire cohort 5 0.9 (0.3–2.1) 1991 1-year exposure; 20-year latency 2 1.2 (0.4–4.2) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 24 1.1 (0.7–1.6) Alavanja et al., 1989 USDA forest or soil conservationists 9 1.0 (0.5–1.9) Henneberger et al., New Hampshire pulp and paper workers 1 0.4 (0.0–2.1) 1989 Alavanja et al., 1988 USDA agricultural extension agents 5 0.6 (0.2–1.3) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 1 1.7 (0.0–9.3) Thomas, 1987 US flavor and fragrance chemical plant workers 6 2.5* Coggon et al., 1986 British MCPA chemical workers (included in the IARC cohort) 8 0.6 (0.3–1.2) Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 14 1.5* Women 2 1.0* Blair et al., 1983 Florida pesticide applicators 2 1.0* Wiklund, 1983 Swedish male and female agricultural workers—incidence 1,083 0.9 (0.9–1.0)d ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Men 21 1.5 (1.0–2.4) Women 24 0.9 (0.6–1.4)

CANCER 307 TABLE 6-8 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Zones A, B—men 9 2.4 (1.2–4.6) women 3 1.1 (0.4–3.5) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone B—men 7 2.9 (1.2–5.9) women 2 1.3 (0.1–4.5) Zone R—men 19 1.1 (0.7–1.8) women 12 0.9 (0.5–1.6) Svensson et al., Swedish fishermen—mortality (men and 1995 women) East coast 4 0.7 (0.2–1.9) West coast 31 1.0 (0.7–1.5) Swedish fishermen—incidence (men and women) East coast 9 0.9 (0.4–1.6) West coast 59 1.1 (0.8–1.4) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—incidence Zone B—men 3 1.4 (0.4–4.4) women 2 1.3 (0.3–5.4) Zone R—men 17 1.1 (0.7–1.9) women 7 0.6 (0.3–1.3) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents—incidence Zones A, B—men 3 1.2 (0.4–3.8) women 2 1.2 (0.3–4.7) Bertazzi et al., Seveso residents—10-year follow-up 1989a Zones A, B, R—men 10 1.0 (0.5–2.0) women 7 1.2 (0.5–2.7) Bertazzi et al., Seveso residents—10-year follow-up 1989b Zone B—men 2 1.7 (0.4–7.0) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 234 1.0 (0.9–1.1) Navy 54 1.1 (0.8–1.4) Army 152 1.0 (0.8–1.1) Air Force 28 1.0 (0.6–1.4) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 69 0.9 (0.7–1.1) Navy 13 0.8 (0.4–1.4) Army 44 0.9 (0.6–1.1) Air Force 12 1.3 (0.6–2.2) continued

308 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-8 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 46 1.4 (0.9–2.2) Mortality 10 1.8 (0.6–5.6) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort (colon, rectum, anus) 9 1.0 (0.4–2.6) Studies Reviewed in Update 2000 AFHS, 2000f Air Force Ranch Hand veterans 7 1.5 (0.4–5.5) AIHW, 1999f Male Australian Vietnam veterans 188 221 expected (191–251) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 16 0.6 (0.4–1.0) CDVA, 1997b Australian National Service Vietnam veterans 3 0.7 (0.2–9.5) Studies Reviewed in VAO Anderson et al., Wisconsin Vietnam veterans 1 — 1986 ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Oc- cupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d 99% CI. e Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity. f Colon and rectal cancer results combined. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort. cancer (SIR 1.20, 95% CI 0.62–2.10) and of rectal cancer (SIR 1.25, 95% CI 0.50–2.58) remained insignificant. In the same cohort, Blair et al. (2005a) found the rate of colon-cancer death reduced in the private applicators (SMR 0.7, 95% CI 0.6–1.0) but slightly increased in their spouses (SMR 1.2, 95% CI 0.8–1.6). Mortality from rectal cancer was not reported separately. In the mortality study of phenoxy herbicide producers and sprayers in New Zealand (’t Mannetje et al., 2005), the data on colon-cancer death (SMR 0.62,

CANCER 309 95% CI 0.08–2.25) and rectal-cancer death (SMR 2.45, 95% CI 0.79–5.73) among producers were indeterminate. In the sprayer group, there were non- significant excesses of cancer deaths from both colon cancer (SMR 1.94, 95% CI 0.84–3.83) and rectal cancer (SMR 1.47, 95% CI 0.40–3.76). Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics reports as having high herbicide use, especially of 2,4-D and MCPA. The esti- mated risk of cancer of the large intestine was reduced (84 cases; SMR 0.57, 95% CI 0.45–0.71). Reif et al. (1989) performed a series of case–control analyses on a sample of 19,904 men entered into the New Zealand Cancer Registry from 1980–1984 with an occupation specified. They focused on the 134 registrants for whom forestry worker (presumed to be exposed to phenoxyherbicides and chlorophenols) was the most recent occupation. Two forestry workers among 63 cases of cancer of the small intestine (OR 5.22, 95% CI 1.44–18.88) represented a significantly increased risk. The seven forestry workers among the 2,043 cases of colon cancer (OR 0.51, 95% CI 0.24–1.09) and the 10 forestry workers among the 1,376 rectal cancer cases (OR 1.22, 95% CI 0.64–2.34) did not constitute excesses. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and colorectal cancer were published since Update 2004. Vietnam-Veteran Studies The 2005 report updating the cancer incidence of Australian Vietnam veterans (ADVA, 2005a) noted a slight increase in the inci- dence of colon cancer (SIR 1.13, 95% CI 1.01–1.24), but no excess of deaths from colon cancer was observed (SMR 0.98, 95% CI 0.83–1.12). The report did not include specific information on the incidence of rectal cancers, but a slight increase in deaths from colorectal cancer was observed (SMR 0.96, 95% CI 0.86–1.06). The incidence of colorectal cancers among deployed National Service veterans (RR 1.13, 95% CI 0.86–1.46) was not increased when compared with that in non-deployed troops, and no excess colorectal deaths were observed (RR 0.80, 95% CI 0.48–1.30) (ADVA, 2005c). In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported nine deaths from cancer of the colon, rectum, or anus (ICD-9 153–154) in the deployed and eight in the non-deployed (CRR 1.02, 95% CI 0.39–2.64). Biologic Plausibility No animal studies have reported an increased incidence of colorectal can- cer after exposure to the compounds of interest. The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter.

310 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis Previous updates have not reviewed the risk of colorectal cancers separately. There has been no evidence to suggest an association between the compounds of interest and colorectal cancer in the epidemiologic studies reviewed to date. The only significant increase in intestinal cancers noted in this update was the reported result concerning cancer of the small intestine that was based on cases in two exposed people (Reif et al., 1989); this is a very uncommon tumor type that is reported here for completeness of coverage with the more common cancers of the large intestine and rectum. There is no evidence of biologic plausibility of an association between exposure to any of the compounds of interest and the development of tumors of the colon or rectum. Overall, the available evidence does not support an association between the compounds of interest and colorectal cancer. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and colorectal cancer. Hepatobiliary Cancers Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). ACS estimated that in 2006 12,600 men and 5,910 women would receive diagnoses of liver or intrahepatic bile duct cancer in the United States and 10,840 men and 5,360 women would die from those cancers (ACS, 2006). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon, but they are often grouped with liver cancers when they are addressed. In the United States, liver cancers account for about 1.3 percent of new cancer cases and 1.2 percent of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to overestimation of the number of deaths attributable to liver cancer (Percy et al., 1990). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. The known risk factors for liver cancer include chronic infection with hepatitis B or C virus and exposure to the carcinogens aflatoxin and vinyl chloride. Alcohol cirrhosis and obesity- associated metabolic syndrome may also contribute to the risk of liver cancer. In the general population, the incidence of liver and intrahepatic bile duct cancer increases slightly with age; at the ages of 50–64 years, it is greater in men than

CANCER 311 in women and greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 6-4. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and hepatobiliary cancers. Additional in- formation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-9 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. The SMR for liver cancer was not associated with a JEM-based estimate of exposure to nonvolatile organochlo- rine compounds (never exposed: 27 cases; SMR 0.87, 95% CI 0.57–1.27; ever exposed: 16 cases; SMR 0.69, 95% CI 0.40–1.13). Alavanja et al. (2005) reported cancer incidence in a prospective cohort study of private pesticide applicators, commercial applicators, and spouses of the private applicators. The risk of liver cancer was effectively unity for the private applicators (SIR 0.98, 95% CI 0.68–1.37) and for their spouses (SIR 0.86, 95% CI 0.17–2.51), as was the risk of gallbladder cancer in the spouses (SIR 0.85, 95% CI 0.17–2.48). An excess of gallbladder cancers (n 8) in the applica- tors approached significance (SIR 2.26, 95% CI 0.87–4.45). Blair et al. (2005a) reported cancer mortality in the same prospective cohort of pesticide applicators and spouses in North Carolina and Iowa. In the applica- tors, mortality from liver cancer was reduced (SMR 0.6, 95% CI 0.2–1.1), but three cases of gallbladder cancer generated an increased risk estimate (SMR 2.0, 95% CI 0.4–5.7). In their spouses, the risks of death from liver cancer (SMR 1.7, 95% CI 0.4–4.3) and gallbladder cancer (SMR 1.3, 95% CI 0.1–4.6) were not increased. In New Zealand, ’t Mannetje et al. (2005) followed the mortality experience of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers from 1969 and 1973, respectively, through 2000. The data on the risk of death from hepatic cancer (ICD-9 155) were uninformative; one death occurred in the producer group and none in the sprayer group. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re- ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of death from liver cancer was significantly reduced in this cohort (15 cases; SMR 0.56, 95% CI 0.31–0.92) when compared with the expected mortality for

312 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-9 Selected Epidemiologic Studies—Hepatobiliary Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 27 0.9 (0.6–1.3) Ever 16 0.7 (0.4–1.1) Alavanja et al., 2005 US Agriculture Health Study—incidence Liver Private applicators (men and women) 35 1.0 (0.7–1.4) Spouses of private applicators ( 99% women) 3 0.9 (0.2–2.5) Commercial applicators (men and women) — 0.0 (0.0–4.2) Gallbladder Private applicators (men and women) 8 2.3 (1.0–4.5) Spouses of private applicators ( 99% women) 3 0.9 (0.2–2.5) Commercial applicators (men and women) — 0.0 (0.0–35.8) Blair et al., 2005a US Agriculture Health Study Liver Private applicators (men and women) 8 0.6 (0.2–1.1) Spouses of private applicators ( 99% women) 4 1.7 (0.4–4.3) Gallbladder Private applicators (men and women) 3 2.0 (0.4–5.7) Spouses of private applicators ( 99% women) 2 1.3 (0.1–4.6) ’t Mannetje et al., New Zealand phenoxy herbicide workers 2005 (ICD-9 155) Producers (men and women) 1 1.6 (0.0–8.8) Sprayers ( 99% men) 0 0.0 (0.0–4.2) Torchio et al., 1994 Italian licensed pesticide users Liver 15 0.6 (0.3–0.9) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) Liver 1 0.8 (0.1–5.8) Gallbladder 3 4.1 (1.4–12.0) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators 0 — Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 7 0.9 (0.4–1.6)

CANCER 313 TABLE 6-9 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Rix et al., 1998 Danish paper mill workers—incidence Liver—men 10 1.1 (0.5–2.0) women 1 0.6 (0.0–3.2) Gallbladder—men 9 1.6 (0.7–3.0) women 4 1.4 (0.4–3.7) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 7 1.3 (0.5–2.6) Kogevinas et al., 1997 IARC cohort (men and women) Workers exposed to any phenoxy herbicide or chlorophenol 15 0.7 (0.4–1.2) Workers exposed to TCDD (or higher- chlorinated dioxins) 12 0.9 (0.5–1.5) Workers not exposed to TCDD (or higher- chlorinated dioxins) 3 0.4 (0.1–1.2) Becher et al., 1996 German production workers (included in the IARC cohort) 1 1.2 (0.0–6.9) Ott and Zober, 1996 BASF employees—incidence 2 2.1 (0.3–7.5) TCDD g/kg of body weight) 0.1 1 2.8 (0.1–15.5) 0.1–0.99 0 0.0 (0.0–15.4) 1 1 2.8 (0.1–15.5) Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 0 —* 15-year latency 0 —* Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide applicators—incidence 3 0.9 (0.2–2.6) Finnish herbicide applicators—mortality 2 0.6 (0.1–2.2) Blair et al., 1993 US farmers in 23 states White men 326 1.0 (0.9–1.1) White women 6 0.7 (0.3–1.6) Collins et al., 1993 Monsanto Company 2,4-D production workers (Included in NIOSH cohort) 2 1.4 (0.2–5.2) Studies Reviewed in VAO Ronco et al., 1992 Danish farm workers—incidence Liver Men—self-employed 23 0.4 (p 0.05) employee 9 0.8 (*) Women—family worker 5 0.5 (*) Gallbladder Men—self-employed 35 0.8 (*) employee 7 0.8 (*) Women—self-employed 7 2.7 (p 0.05) employee 1 0.7 (*) family worker 17 1.0 (*) continued

314 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-9 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Fingerhut et al., 1991 NIOSH—entire cohort (liver and biliary) 6 1.2 (0.4–2.5) 1-year exposure; 20-year latency 1 0.6 (0.0–3.3) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 4 0.4 (0.1–1.1) Solet et al., 1989 US pulp and paper workers 2 2.0 (0.2–7.3) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0 1.2 (*) Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 3 1.0 (*) Women 0 — Hardell et al., 1984 Swedish residents—incidence and mortality combined 102 1.8 (0.9–4.0) Wiklund, 1983 Swedish male and female agricultural workers—incidence Liver (primary) 103 0.3 (0.3–0.4)d Biliary passages 169 0.6 (0.5–0.7) Liver (unspecified) 67 0.9 (0.7–1.3) Zack and Suskind, Monsanto Company production workers 1980 (Included in NIOSH cohort) 0 —* ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Zone A, B—men (liver, gallbladder) 6 0.5 (0.2–1.0) (liver) 6 0.5 (0.2–1.1) women (liver, gallbladder) 7 1.0 (0.5–2.2) (liver) 6 1.3 (0.6–2.9) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone B—men (liver, gallbladder) 4 0.6 (0.2–1.4) (liver) 4 0.6 (0.2–1.6) women (liver, gallbladder) 4 1.1 (0.3–2.9) (liver) 3 1.3 (0.3–3.8) Zone R—men (liver, gallbladder) 35 0.7 (0.5–1.0) (liver) 31 0.7 (0.5–1.0) women (liver, gallbladder) 25 0.8 (0.5–1.3) (liver) 12 0.6 (0.3–1.1)

CANCER 315 TABLE 6-9 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Svensson et al., 1995 Swedish fishermen—mortality (men and women) East coast 1 0.5 (0.0–2.7) West coast (liver and bile ducts) 9 0.9 (0.4–1.7) Swedish fishermen—incidence (men and women) East coast 6 1.3 (0.5–2.9) West coast (liver and bile ducts) 24 1.0 (0.6–1.5) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—incidence Zone B—men (liver) 4 2.1 (0.8–5.8) (gallbladder) 1 2.3 (0.3–17.6) women (gallbladder) 4 4.9 (1.8–13.6) Zone R—men (liver) 3 0.2 (0.1–0.7) (gallbladder) 3 1.0 (0.3–3.4) women (liver) 2 0.5 (0.1–2.1) (gallbladder) 7 1.0 (0.5–2.3) Cordier et al., 1993 Military service in South Vietnam for 10 years after 1960 11 8.8 (1.9–41.0) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents—incidence Zone A, B—men (liver) 4 1.5 (0.5–4.0) (gallbladder) 1 2.1 (0.3–15.6) women (liver) 1 1.2 (0.2–9.1) (gallbladder) 5 5.2 (2.1–13.2) Zone R—men (liver) 8 0.5 (0.2–0.9) (gallbladder) 3 1.0 (0.3–3.4) women (liver) 5 0.8 (0.3–2.1) (gallbladder) 7 1.0 (0.5–2.3) Bertazzi et al., 1989b Seveso residents—10-year follow-up Zone A—women (gallbladder) 1 12.1 (1.6–88.7) Zone B—men (liver) 3 1.2 (0.4–3.8) women (gallbladder) 2 3.9 (0.9–16.2) Zone R—men (liver) 7 0.4 (0.2–0.8) women (liver) 3 0.4 (0.1–1.4) (gallbladder) 5 1.2 (0.5–3.1) Hoffman et al., 1986 Residents of Quail Run Mobile Home Park (men and women) 0 * continued

316 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-9 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 27 0.7 (0.4–1.0) Navy 8 1.0 (0.4–1.9) Army 18 0.7 (0.4–1.1) Air Force 1 0.2 (0.0–1.2) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality (liver and gallbladder) 48 0.9 (0.6–1.1) Navy 11 1.0 (0.5–1.7) Army 33 0.9 (0.6–1.2) Air Force 4 0.6 (0.2–1.5) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 2 2.5 (0.1–147.2) Mortality (liver and gallbladder) 4 2.5 (0.4–27.1) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience 5 —* Cohort (liver) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 2 1.6 (0.2–11.4) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans Liver 8 0.6 (0.2–1.1) Gallbladder 5 1.3 (0.4–2.8) CDVA, 1997b Australian National Service Vietnam veterans 1 —* Studies Reviewed in VAO CDC, 1990a US men born 1921–1953 8 1.2 (0.5–2.7) Breslin et al., 1988 Army Vietnam veterans (liver and bile duct) 34 1.0 (0.8–1.4) Marine Vietnam veterans (liver and bile duct) 6 1.2 (0.5–2.8) Anderson et al., 1986b Wisconsin Vietnam veterans 0 —* ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ADVA, Australian Department of Vet- eran Affairs; AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health, TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d 99% CI. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort.

CANCER 317 the regional and provincial population. The authors suggested that the relatively short duration of follow-up and the healthy-worker effect contributed to the ob- servation of reduced mortality. Reif et al. (1989) performed a series of case–control analyses on a sample of 19,904 men entered into the New Zealand Cancer Registry from 1980–1984 with an occupation specified. They focused on the 134 registrants for whom forestry worker (presumed to be exposed to phenoxyherbicides and chlorophenols) was the most recent occupation. A single forestry worker among the 184 cases with cancer of the liver did not constitute an excess (OR 0.81, 95% CI 0.11–5.8). However, three forestry workers were among the 120 cases of gallbladder cancer (OR 4.13, 95% CI 1.42–12.04) in the cohort. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and hepatobiliary cancer were published since Update 2004. Vietnam-Veteran Studies In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported five deaths from cancer of the liver or in- trahepatic bile ducts (ICD-9 155) in the deployed and three in the non-deployed. The researchers did not consider the data sufficient for the calculation of risk statistics unless there were at least 10 deaths from a type of cancer. A set of three reports updating the health status of Australian Vietnam vet- erans noted results concerning possible associations between Vietnam service and the incidence of liver cancer and mortality from liver and gallbladder cancer. The incidence of liver cancer was lower in Vietnam veterans than in the general population (SIR 0.70, 95% CI 0.44–0.97) (ADVA, 2005a), and there was no increase in the risk of death from liver or gallbladder cancer (SMR 0.88, 95% CI 0.63–1.13) (ADVA, 2005b). In a third report on the potential for a healthy- warrior effect, there were too few incident cases of liver cancer (n 2) to calcu- late stable estimates (RR 2.50, 95% CI 0.13–147); that was also the case for mortality from liver or gallbladder cancer (n 4; RR 2.45, 95% CI 0.35–27.06) (ADVA, 2005c). Biologic Plausibility A recent study used a mouse model bearing a constitutively active form of the AhR to examine the role of the AhR in promotion of hepatocarcinogenesis; treatment with the tumor initiator N-nitrosodiethylamine resulted in an increase in hepatic tumors that was significantly greater than that observed in the wild-type mice (Moennikes et al., 2004). The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter.

318 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis In this update, no new reports of a definitive link between exposure to the compounds of interest and hepatobiliary tumors were found. One study suggested a reduced risk of hepatic cancers in veteran populations, and one suggested an in- creased risk of cancer of the gallbladder among forestry workers. However, given the relatively low incidence of hepatobiliary cancers in Western populations, the evidence from epidemiologic studies remains inadequate to link the compounds of interest with hepatobiliary cancer. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and hepatobiliary cancer. The evidence regarding associa- tion is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Although several of those studies involved sizable cohorts, hepatobiliary cancers are rare, and the power of the studies to detect an increase in incidence is low. Pancreatic Cancer The incidence of pancreatic cancer (ICD-9 157) increases with age. ACS estimated that 17,150 men and 16,580 women would develop pancreatic cancer in the United States in 2006 and that 16,090 men and 16,210 women would die from it (Jemal et al., 2006). The incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history, diet, and tobacco use; the incidence is about twice as high in smokers as in nonsmokers (Miller et al., 1996). Chronic pancreatitis, obesity, and type 2 diabetes are also associated with an increased risk of pancreatic cancer (ACS, 2006). Conclusions from VAO and Updates This update considers pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer, but conclusions about the adequacy of the evidence of its association with herbicide exposure have been reached in the context of gastrointestinal tract cancers. Table 6-10 sum- marizes the results of the relevant studies concerning pancreatic cancer. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. The SMR for pancreatic cancer

CANCER 319 TABLE 6-10 Selected Epidemiologic Studies—Pancreatic Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 67 0.8 (0.7–1.1) Ever 69 1.1 (0.9–1.4) Alavanja et al., 2005 US Agriculture Health Study—incidence Private applicators (men and women) 46 0.7 (0.5–1.0) Spouses of private applicators ( 99% women) 20 0.9 (0.6–1.4) Commercial applicators (men and women) 3 1.1 (0.2–3.2) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) 29 0.6 (0.4–0.9) Spouses of private applicators ( 99% women) 10 0.7 (0.3–1.2) ’t Mannetje et al., 2005 Phenoxy herbicide producers (men and women) 3 2.1 (0.4–6.1) Phenoxy herbicide sprayers ( 99% men) 0 0.0 (0.0–2.1) Torchio et al., 1994 Italian licensed pesticide users 32 0.7 (0.5–1.0) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 6 1.8 (0.8–4.1) Magnani et al., 1987 UK case–control Herbicides * 0.7 (0.3–1.5) Chlorophenols * 0.8 (0.5–1.4) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators 5 1.2 (0.4–2.7) Studies Reviewed in Update 2000 Ojajärvi et al., 2000 Meta-analysis of 161 populations 127 MRR 1.0 (0.8–1.3) Steenland et al., 1999 US chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 16 1.0 (0.6–1.6) Hooiveld et al., 1998 Dutch chemical production workers (included in the IARC cohort) 4 2.5 (0.7–6.3) Rix et al., 1998 Danish paper mill workers—incidence Men 30 1.2 (0.8–1.7) Women 2 0.3 (0.0–1.1) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 7 0.9 (0.4–1.9) continued

320 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-10 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Kogevinas et al., 1997 IARC cohort (men and women) Workers exposed to any phenoxy herbicide or chlorophenol 47 0.9 (0.7–1.3) Exposed to TCDD (or higher- chlorinated dioxins) 30 1.0 (0.7–1.4) Not exposed to TCDD (or higher- chlorinated dioxins) 16 0.9 (0.5–1.4) Becher et al., 1996 German production workers (included in the IARC cohort) Plant I 2 0.6 (0.1–2.3) Plant II 0 — Plant III 0 — Plant IV 2 1.7 (0.2–6.1) Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 2 0.7 (0.1–2.7) 15-year latency 2 0.9 (0.1–3.3) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 1,133 1.1 (1.1–1.2) White women 23 1.0 (0.6–1.5) Bueno de Mesquita Dutch phenoxy herbicide workers (included 3 2.2 (0.5–6.3) et al., 1993 in the IARC cohort) Studies Reviewed in VAO Ronco et al., 1992 Danish farm workers—incidence Men—self-employed 137 0.6 (p 0.05) employee 23 0.6 (p 0.05) Women—self-employed 7 1.2 (*) employee 4 1.3 (*) family worker 27 0.7 (p 0.05) Swaen et al., 1992 Dutch licensed herbicide applicators 3 2.2 (0.4–6.4) Fingerhut et al., 1991 NIOSH—entire cohort 10 0.8 (0.4–1.6) 1-year exposure; 20-year latency 4 1.0 (0.3–2.5) Saracci et al., 1991 IARC cohort—exposed subcohort (men and 26 1.1 (0.7–1.6) women) Alavanja et al., 1989 USDA forest or soil conservationists 22 1.5 (0.9–2.3) Henneberger et al., 1989 New Hampshire paper and pulp workers 9 1.9 (0.9–3.6) Solet et al., 1989 US pulp and paper workers 1 0.4 (0.0–2.1) Alavanja et al., 1988 USDA agricultural extension agents 21 1.3 (0.8–1.9) Thomas, 1987 US flavor and fragrance chemical plant 6 1.4* workers Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) 9 0.7 (0.3–1.4) Robinson et al., 1986 Northwestern US paper and pulp workers 4 0.3 (0.1–0.8)d

CANCER 321 TABLE 6-10 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 3 0.6* Women 0 — Blair et al., 1983 Florida pesticide applicators 4 4.0 Expected* Wiklund, 1983 Swedish male and female agricultural workers—incidence 777 0.8 (0.8–0.9)e Burmeister, 1981 Iowa farmers 416 1.1* ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Zones A, B—men 4 0.7 (0.3–1.9) women 1 0.3 (0.0–2.0) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone A—men 1 1.9 (0.0–10.5) Zone B—men 2 0.6 (0.1–2.0) women 1 0.5 (0.0–3.1) Zone R—men 20 0.8 (0.5–1.2) women 11 0.7 (0.4–1.3) Svensson et al., 1995 Swedish fishermen—mortality (men and women) East coast 5 0.7 (0.2–1.6) West coast 33 0.8 (0.6–1.2) Swedish fishermen—incidence (men and women) East coast 4 0.6 (0.2–1.6) West coast 37 1.0 (0.7–1.4) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents—incidence Zones A, B—men 2 1.0 (0.3–4.2) women 1 1.6 (0.2–12.0) Bertazzi et al., 1989a Seveso residents—10-year follow-up Zones A, B, R—men 9 0.6 (0.3–1.2) women 4 1.0 (0.3–2.7) Bertazzi et al., 1989b Seveso residents—10-year follow-up Zone B—men 2 1.1 (0.3–4.5) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 86 1.2 (0.9–1.4) Navy 14 0.9 (0.5–1.5) Army 60 1.2 (0.9–1.5) Air Force 12 1.3 (0.7–2.3) continued

322 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-10 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 101 1.2 (1.0–1.5) Navy 18 1.0 (0.6–1.6) Army 71 1.3 (1.0–1.6) Air Force 11 1.1 (0.5–1.8) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 17 2.5 (1.0–6.3) Mortality 19 3.1 (1.3–8.3) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience 5 1.0 (0.3–3.5) Cohort Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 38 1.4 (0.9–1.8) CDVA, 1997b Australian National Service Vietnam veterans 6 1.5 Studies Reviewed in Update 1996 Dalager et al., 1995 US Vietnam veterans—women 7 2.8 (0.8–10.2) Vietnam veteran nurses 7 5.7 (1.2–27.0) Visintainer et al., 1995 Michigan Vietnam veterans 14 1.0 (0.6–1.7) Studies Reviewed in VAO Thomas et al., 1991 US Vietnam veterans—women 5 2.7 (0.9–6.2) Breslin et al., 1988 Army Vietnam veterans 82 0.9 (0.6–1.2) Marine Vietnam veterans 18 1.6 (0.5–5.8) Anderson et al., 1986b Wisconsin Vietnam veterans 4 — ABBREVIATIONS: ADVA, Australian Department of Veteran Affairs; CDVA, Commonwealth De- partment of Veterans’ Affairs; CI, confidence interval; IARC; International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupa- tional Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d 90% CI. e 99% CI. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohort. was not associated with a JEM-based estimate of exposure to nonvolatile organo- chlorine compounds (never exposed: 67 cases; SMR 0.84, 95% CI 0.65–1.06; ever exposed: 69 cases; SMR 1.12, 95% CI 0.87–1.42). In the AHS study of cancer incidence, Alavanja et al. (2005) reported a slight decrease in the incidence of pancreatic cancer in private applicators (SIR

CANCER 323 0.73, 95% CI 0.53–0.97) and no increase in their spouses (SIR 0.92, 95% CI 0.56–1.42). In the commercial applicators, the findings on pancreatic cancer were indeterminate; there were only three cases. In investigating cancer mortality in the same prospective cohort study of private pesticide applicators and their spouses, Blair et al. (2005a) found that the rates of pancreatic cancer were reduced in both the applicators (SMR 0.6, 95% CI 0.4–0.9) and their spouses (SMR 0.7, 95% CI 0.3–1.2). The similarity to the results reported by Alavanja et al. (2005) is not unexpected, because median survival of pancreatic cancer is only about 3–6 months. In the mortality study of phenoxy herbicide producers and sprayers in New Zealand (’t Mannetje et al., 2005), only three cases of pancreatic cancer were observed in the producer group and none in the sprayer group. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics reports as having high herbicide use, especially of 2,4-D and MCPA. The esti- mated risk of pancreatic cancer was significantly reduced (32 cases; SMR 0.7, 95% CI 0.48–0.99). The authors suggested that the relatively short duration of follow-up and the healthy-worker effect contributed to the observation of reduced mortality. Starting with the 19,904 men entered into the the New Zealand Cancer Reg- istry from 1980–1984 with a specified occupation, Reif et al. (1989) contrasted the 571 cases of pancreatic cancer with the remaining subjects having other types of cancer. Of the 134 cancer registrants for whom forestry worker (with presumed exposure to phenoxy herbicides and chlorophenols) was the most recent occupa- tion, the proportion with pancreatic cancer was not significantly elevated (6 cases; OR 1.79, 95% CI 0.79–4.05). Magnani et al. (1987) reported a case–control mortality study of 343 pancre- atic-cancer cases and 1,315 controls in the United Kingdom. A JEM was used to predict exposures to various chemical agents on the basis of job title as indicated on the death certificates. Estimated risks of pancreatic cancer associated with exposure to herbicides (RR 0.7, 95% CI 0.3–1.5) and chlorophenols (RR 0.8, 95% CI 0.5–1.4) were not significantly increased. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and pancreatic cancer were published since Update 2004. Vietnam-Veteran Studies In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported five pancreatic-cancer deaths in the de- ployed and five in the non-deployed (CRR 1.02, 95% CI 0.29–3.53). A set of three reports updating the health status of Australian Vietnam vet- erans noted 86 cases of pancreatic cancer (SIR 1.15, 95% CI 0.91–1.40) (ADVA, 2005a) and 101 deaths (SMR 1.21, 95% CI 0.97–1.45) (ADVA,

324 VETERANS AND AGENT ORANGE: UPDATE 2006 2005b). However, in the report on the health of National Service veterans and non-deployed troops, the incidence of pancreatic cancer was much higher in deployed National Service veterans than in non-deployed veterans (RR 2.46, 95% CI 1.04–6.27), and mortality from pancreatic cancer was also higher (RR 3.13, 95% CI 1.31–8.26) (ADVA, 2005c). Information on the smoking status of neither National Service veterans nor non-deployed troops was available, but the investigators postulate that given the increased rates of lung, head, and neck cancers in the National Service veterans, those veterans might have higher rates of smoking than the non-deployed controls (ADVA, 2005c). Biologic Plausibility A 2-year study of female rats has reported increased incidences of pancre- atic adenomas and carcinomas after treatment at the highest dose of TCDD (100 ng/kg per day) (Nyska et al., 2004). Chronic active inflammation, acinar-cell vacuolation, and an increase in proliferation of the acinar cells surrounding the vacuolated cells have been observed (Yoshizawa et al., 2005b). Synthesis The increased rates of pancreatic cancer among Australian Vietnam National Service veterans could be associated with increased rates of smoking and cannot be attributed to exposure to the compounds of interest. All other reports have been largely negative except the report of seven cases of pancreatic cancer (RR 5.7, 95% CI 1.2–27) in US Vietnam female nurse veterans (Dalager et al., 1995). Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and pancreatic cancer. Conclusions on All Cancers of the Digestive Organs The original VAO report (IOM, 1994) considered “gastrointestinal tract tu- mors” as a group—which explicitly included stomach, colon, rectal, and pancre- atic cancers—and concluded that there was suggestive evidence of no association with herbicide exposure. Cumulative results tables have been maintained for these four cancer sites, and another was added for esophageal cancer in Update 2004, but until now a global conclusion has been reached on gastrointestinal cancers overall while cancers associated with the liver have been considered sepa- rately. The committee decided to appraise the evidence separately for esophageal,

CANCER 325 stomach, colorectal, pancreatic, and hepatobiliary cancer to address VA’s concern that all types of cancer be reported on with the greatest degree of specificity pos- sible and to implement its own conviction that the tissues along the span of the digestive tract are likely to vary in their risk factors and responses to carcinogens. Drawing discrete conclusions is somewhat complicated because reported results on those sites are grouped in a variety of ways that may be influenced by the nature of the observed results in a given study. For each of the cancer types previously grouped as “gastrointestinal tract tumors” with a categorization of limited or suggestive evidence of no association with exposure to the compounds of interest, this committee does conclude, how- ever, that there is inadequate or insufficient evidence to support an association. There is not enough evidence to support an assertion about association, either positive or negative, with phenoxy herbicides or dioxin; and virtually no data are available on human response to cacodylic acid or picloram, so an assertion of no association with these two substances is not sustainable either. LARYNGEAL CANCER ACS estimated that 7,700 men and 1,810 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2006 and 2,950 men and 790 women would die from it (Jemal et al., 2006). Those numbers constitute a little more than 0.7 percent of new cancer diagnoses and deaths. The incidence of cancer of the larynx increases with age, and it is more common in men than in women, with a sex ratio in the United States of about 4:1 among persons 50–64 years old. The average annual incidence of laryngeal cancer is shown in Table 6-11. Established risk factors for laryngeal cancer are tobacco and alcohol use, which are independent and act synergistically. Occupational exposures—long and intense exposures to wood dust, paint fumes, and some chemicals—also could increase risk (ACS, 2007b). An IOM committee (2006) recently concluded that asbestos is a causal factor in laryngeal cancer (IOM, 2006); infection with human TABLE 6-11 Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Men 10.4 9.7 21.9 15.8 15.4 28.3 24.1 24.4 38.0 Women 2.2 2.2 4.1 3.5 3.4 6.8 5.1 5.1 10.1 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

326 VETERANS AND AGENT ORANGE: UPDATE 2006 papilloma virus (HPV) might also raise the risk of laryngeal cancer (Hobbs and Burchall, 2004). Conclusions from VAO and Updates The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and laryngeal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-12 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. The SMR for cancer of the larynx was not as- sociated with a JEM-based estimate of exposure to nonvolatile organochlorine compounds (never exposed: 18 cases; SMR 0.92, 95% CI 0.54–1.45; ever exposed: 20 cases; SMR 1.23, 95% CI 0.75–1.90). In New Zealand, ’t Mannetje et al. (2005) followed the mortality experience of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers from 1969 and 1973, respectively, through 2000. Laryngeal cancers were grouped with re- spiratory cancers (ICD-9 160–165; n 13); from the results for the subcategories, “trachea, bronchus, lung” (ICD-9 162; n 12) and “other” (ICD-9 163–165; n 1), it is evident that no laryngeal cancer deaths (ICD-9 161) were observed in either the producer or the sprayer group. Torchio et al. (1994) reported on the mortality experience of a cohort of 23,401 male farmers in the Piedmont area of Italy from the time they registered to use agricultural pesticides (1970–1974) through 1986. Those provinces are characterized by higher use of herbicides, particularly 2,4-D and MCPA, than the rest of the country. Mortality from laryngeal cancer was significantly lower in the farmers than in the regional population (SMR 0.46, 95% CI 0.30–0.67). Reif et al. (1989) performed a series of case–control analyses on the sample of 19,904 people with specified occupations among the 24,762 men 20 years old or older entered from 1980 to 1984 into the the New Zealand Cancer Registry. The focus of their study was on the 134 for whom forestry work was the most recent occupation listed. For each type of cancer, those with any other type of cancer were used as controls. Of 303 people with laryngeal cancer, two had most recently been forestry workers (OR 1.14, 95% CI 0.28–4.65).

CANCER 327 TABLE 6-12 Selected Epidemiologic Studies—Laryngeal Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 18 0.9 (0.5–1.5) Ever 20 1.2 (0.8–1.9) ’t Mannetje et al., Phenoxy herbicide producers (men and women) 0 * 2005 Phenoxy herbicide sprayers ( 99% men) 0 * Torchio et al., 1994 Italian farmers licensed to use pesticides 25 0.5 (0.3–0.7) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 2 1.1 (0.3–4.7) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators 1 1.0 (0.0–5.1) Studies Reviewed in Update 2002 Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides Foremen—incidence 0 * Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 7 0.9 (0.4–1.9) Kogevinas et al., IARC cohort (men and women) 21 1.6 (1.0–2.5) 1997 Workers exposed to any phenoxy herbicide or chlorophenol 21 1.6 (1.0–2.5) Exposed to TCDD (or higher-chlorinated dioxins) 15 1.7 (1.0–2.8) Not exposed to TCDD (or higher-chlorinated dioxins) 5 1.2 (0.4–2.9) Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 2 2.9 (0.3–10.3) 0-year latency 2 2.9 (0.4–10.3) 15-year latency 1 — Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 162 0.7 (0.6–0.8) White women 0 — (0.0–3.3) Studies Reviewed in VAO Fingerhut et al., NIOSH—entire cohort 7 2.1 (0.8–4.3) 1991 1-year exposure, 20-year latency 3 2.7 (0.6–7.8) Manz et al., 1991 German production workers—men and women (included in the IARC cohort) 2 2.0 (0.2–7.1) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 8 1.5 (0.6–2.9) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 1 3.0 (0.0–16.8) continued

328 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-12 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) 4 2.3 (0.5–4.5) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Men 13 2.3 (1.2–3.8) Women 1 0.1 (0.0–0.6) Studies Reviewed in Update 2000 Bertazzi et al., 2001d Seveso residents—20-year follow-up Zone A, B—men 64 1.3 (1.0–1.6) women 5 0.7 (0.3–1.7) Bertazzi et al., 1998e Seveso residents—15-year follow-up Zone B—men 40 1.2 (0.9–1.7) women 2 0.5 (0.1–2.0) Zone R—men 208 0.9 (0.8–1.1) women 35 1.1 (0.8–1.5) VIETNAM VETERANS New Studies ADVA, 2005a Australian Vietnam veterans vs Australian population—incidence 97 1.5 (1.2–1.8) Navy 21 1.5 (0.9–2.1) Army 69 1.6 (1.2–1.9) Air Force 7 0.8 (0.3–1.7) ADVA, 2005b Australian Vietnam veterans vs Australian population—mortality 28 1.1 (0.7–1.5) Navy 6 1.1 (0.4–2.4) Army 19 1.1 (0.7–1.7) Air Force 3 0.8 (0.2–2.5) ADVA, 2005c Australian men conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence 8 0.7 (0.2–1.6) Mortality 2 0.4 (0.0–2.4) Boehmer et al., 2004 CDC Vietnam Experience Cohort 0 0 (*) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans Oral cavity, pharynx, and larynx 4 0.6 (0.2–2.4) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 12 1.3 (0.7–2.2) CDVA, 1997b Australian National Service Vietnam veterans 0 0 (0– 10)

CANCER 329 TABLE 6-12 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Watanabe and Kang, Army Vietnam veterans compared with US men 50 1.3* 1996 Marine Vietnam veterans 4 0.7* Army Vietnam veterans 50 1.4e ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ADVA, Australian Department of Vet- eran Affairs; AFHS, Air Force Health Study; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4- chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d Report did not separate laryngeal from lung and other respiratory cancers. e Statistically significant with the 95% CI not including 1.0. * Information not provided by study authors. Studies in italics have been superseded by newer studies of the same cohorts. Environmental Studies No relevant environmental studies concerning exposure to the compounds of interest and laryngeal cancer were published since Update 2004. Vietnam-Veteran Studies In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported no deaths from laryngeal cancer in the deployed and two in the non- deployed. (The researchers estimated rate ratios only for sites of cancer with 10 or more deaths.) A series of reports providing updates on the health status of Australian Vietnam veterans found a significant association with the incidence of laryngeal cancer (SIR 1.46, 95% CI 1.17–1.75) (ADVA, 2005a) but not with mortality from laryngeal cancer (SMR 1.09, 95% CI 0.69–1.49) (ADVA, 2005b) when comparing veterans with the general population. When Australian veterans de- ployed to Vietnam were compared with those not deployed there, however, both laryngeal-cancer incidence and mortality were non-significantly reduced (RR 0.65, 95% CI 0.24–1.60 and RR 0.42, 95% CI 0.04–2.37, respectively [ADVA, 2005c]).

330 VETERANS AND AGENT ORANGE: UPDATE 2006 Biologic Plausibility No animal studies have identified an association between exposure to the compounds of interest and an increased incidence of laryngeal cancer. The bio- logic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis Only three reports (all on Australian Vietnam veterans) published since Up- date 2004 provided any useful data regarding the association between exposure to the compounds of interest and laryngeal cancer. Only in the study of cancer incidence compared with the general population was the rate of laryngeal cancer convincingly increased (ADVA, 2005a), but the study that included a reference group for comparing Vietnam-era veterans did not support the hypothesis that the increase was associated with having been in Vietnam (ADVA, 2005a). The conclusion that there is limited or suggestive evidence of an association between exposure to the compounds of interest and laryngeal cancer is not affected by the results of the new studies. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evi- dence of an association between exposure to at least one compound of interest and laryngeal cancer. LUNG CANCER Lung cancer (carcinomas of the lung and bronchus, ICD-9 162.2–162.9) is the leading cause of cancer death in the United States. ACS estimated that 92,700 men and 81,770 women would receive diagnoses of lung cancer in the United States in 2006 and about 90,330 men and 72,130 women would die from it (Jemal et al., 2006). Those numbers represent roughly 12.5 percent of new cancer diag- noses and 29 percent of cancer deaths in 2006. The principal types of lung neo- plasms are identified collectively as bronchogenic carcinoma (the bronchi are the two main branches of the trachea) and carcinoma of the lung. The trachea (ICD-9 162.0) is frequently grouped with the lung and bronchus under ICD-9 162. The lung is also a common site of the development of metastatic tumors. In men and women, the incidence of lung cancer increases greatly beginning at about the age of 40 years. The incidence in people 50–54 years old is double that in people 45–49 years old, and it doubles again in those 55–59 years old. The incidence is consistently higher in black men than in women or white men.

CANCER 331 The average annual incidence of lung cancer in the United States is shown in Table 6-13. ACS estimates that more than 90 percent of lung cancers in men are attrib- utable to tobacco use (ACS, 1998). Smoking increases the risk of all histologic types of lung cancer, although the associations with squamous-cell and small-cell carcinomas are strongest. Other risk factors include exposure to asbestos, ura- nium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic (this does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can also be assumed to be a risk factor). Important environmental risk factors include exposure to tobacco smoke and radon (ACS, 2007c). Conclusions from VAO and Updates The committee responsible for VAO concluded that there was limited or sug- gestive evidence of an association between exposure to at least one compound of interest and lung cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-14 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. The SMR of lung cancer was not associated with a JEM-based estimate of exposure to nonvolatile organochlorine compounds (never exposed: 356 cases; SMR 0.98, 95% CI 0.88–1.08; ever exposed: 314 cases; SMR 1.04, 95% CI 0.93–1.17). TABLE 6-13 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Men 58.9 54.0 123.2 123.1 114.2 244.5 230.6 224.9 362.8 Women 46.7 47.0 67.0 96.0 98.2 125.5 159.3 168.3 177.6 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

332 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-14 Selected Epidemiologic Studies—Lung and Bronchus Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers— exposure to nonvolatile organochlorine compounds Lung (ICD-9 162) Never 356 1.0 (0.9–1.1) Ever 314 1.0 (0.9–1.2) Pleura (ICD-9 163) Never 17 2.8 (1.6–4.5) Ever 4 0.8 (0.2–2.0) Other Respiratory (ICD-9 164–165) Never 8 2.1 (0.9–4.2) Ever 2 0.7 (0.1–2.4) Alavanja et al., 2005 US Agriculture Health Study—incidence (lung) Private applicators (men and women) 266 0.5 (0.4–0.5) Spouses of private applicators ( 99% women) 68 0.4 (0.3–0.5) Commercial applicators (men and women) 12 0.6 (0.3–1.0) Blair et al., 2005a US Agriculture Health Study (lung) Private applicators (men and women) 129 0.4 (0.3–0.4) Years handled pesticides 10 years 25 0.4* (p 0.05) 10 years 80 0.3* (p 0.05) Spouses of private applicators ( 99% women) 29 0.3 (0.2–0.5) ’t Mannetje et al., New Zealand phenoxy herbicide workers 2005 (trachea, bronchus, lung) Producers (men and women) 12 1.4 (0.7–2.4) Sprayers ( 99% men) 5 0.5 (0.2–1.1) Torchio et al., 1994 Italian licensed pesticide users 155 0.5 (0.4–0.5) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 30 1.3 (0.8–1.9) Studies Reviewed in Update 2004 Bodner et al., 2003 Dow chemical production workers— lung (included in the IARC cohort and the NIOSH Dioxin Registry) 54 0.8 (0.6–1.1) Swaen et al., 2004 Dutch licensed herbicide applicators (trachea and lung) 27 0.7 (0.5–1.0) Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4–D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) Respiratory system 31 0.9 (0.6–1.3)

CANCER 333 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Thörn et al., 2000 Swedish lumberjacks exposed to phenoxy herbicides Foremen—incidence (bronchus and lung) 1 4.2 (0.1–23.2) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers—lung (included in the IARC cohort and the NIOSH Dioxin Registry) 125 1.1 (0.9–1.3) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers (lung) 45 0.8 (0.6–1.1) Kogevinas et al., 1997 IARC cohort (men and women, lung) Workers exposed to any phenoxy herbicide or chlorophenol 380 1.1 (1.0–1.2) Exposed to TCDD (or higher- chlorinated dioxins) 225 1.1 (1.0–1.3) Not exposed to TCDD (or higher- chlorinated dioxins) 148 1.0 (0.9–1.2) Becher et al., 1996 German production workers (included in the IARC cohort) (lung) 47 1.4 (1.1–1.9) Ott and Zober, 1996 BASF employees—incidence Respiratory system 13 1.2 (0.6–2.0) TCDD ( g/kg of body weight) 0.1–0.99 2 0.7 (0.1–2.5) 1 8 2.0 (0.9–3.9) Lung or bronchus 11 1.1 (0.6–2.0) TCDD ( g/kg of body weight) 0.1–0.99 2 0.8 (0.1–2.8) 1 8 2.2 (1.0–4.3) Ramlow et al., 1996 Dow pentachlorophenol production workers—respiratory system (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 18 1.0 (0.6–1.5) 15-year latency 17 1.1 (0.6–1.8) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide applicators 1972–1989 (trachea, bronchus, lung) Incidence 39 0.9 (0.7–1.3) Mortality 37 1.0 (0.7–1.4) Blair et al., 1993 US farmers from 23 states (lung) White men 6,473 0.9 (0.9–0.9) White women 57 0.8 (0.6–1.1) Bloemen et al., 1993 Dow 2,4-D production workers—respiratory system (included in the IARC cohort and the NIOSH Dioxin Registry) 9 0.8 (0.4–1.5) continued

334 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Kogevinas et al., 1993 IARC cohort, women (lung)—incidence 2 1.4 (0.2–4.9) Lynge, 1993 Danish production workers, men (lung)— incidence (included in the IARC cohort) 13 1.6 (0.9–2.8) Studies Reviewed in VAO Bueno de Mesquita Dutch phenoxy herbicide workers (included et al., 1993 in the IARC cohort) (trachea, bronchus, lung) 9 0.8 (0.4–1.5) Swaen et al., 1992 Dutch herbicide applicators (trachea and lung) 12 1.1 (0.6–1.9) Coggon et al., 1991 British phenoxy herbicide workers (lung) (included in the IARC cohort) 19 1.3 (0.8–2.1) Workers with exposure above background levels 14 1.2 (0.7–2.1) Fingerhut et al., 1991 NIOSH—entire cohort (trachea, bronchus, lung) 89 1.1 (0.9–1.4) 1-year exposure; 20-year latency 40 1.4 (1.0–1.9) Green, 1991 Herbicide sprayers in Ontario (lung) 5 * Manz et al., 1991 German production workers, men (lung) (included in the IARC cohort) 26 1.7 (1.1–2.4) Saracci et al., 1991 IARC cohort, men and women (trachea, bronchus, lung) 173 1.0 (0.9–1.2) McDuffie et al., 1990 Saskatchewan farmers applying herbicides (lung) 103 0.6 (* NS) Zober et al., 1990 BASF employees (trachea, bronchus, lung)—incidence 4 2.0 (0.7–4.6) Bender et al., 1989 Herbicide sprayers in Minnesota (trachea, bronchus, lung) 54 0.7 (0.5–0.9) Wiklund et al., 1989a Swedish pesticide applicators (trachea, bronchus, lung) 38 0.5 (0.4–0.7) Bond et al., 1988 Dow 2,4-D production workers—lung (included in the IARC cohort and the NIOSH Dioxin Registry) 8 1.0 (0.5–2.0) Low cumulative exposure 1 0.7 (* NS) Medium cumulative exposure 2 1.0 (* NS) High cumulative exposure 5 1.7 (* NS) Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) (lung, pleura, and retroperitoneal) 117 1.2 (1.0–1.4) Background exposure 39 1.0 (0.7–1.4) Low-grade exposure 35 1.1 (0.8–1.6) High-grade exposure 43 1.3 (1.0–1.8) Lynge, 1985 Danish production workers—lung, incidence (included in the IARC cohort) Men 38 1.2* Women 6 2.2*

CANCER 335 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Blair et al., 1983 Licensed pesticide applicators in Florida, lawn and ornamental pest category only (lung) 7 0.9* Axelson et al., 1980 Swedish herbicide sprayers (lung) 3 1.4* ENVIRONMENTAL Studies Reviewed in Update 2004 Fukuda et al., 2003 Residents of municipalities in Japan with vs without waste incineration plants (lung) Age-adjusted mortality (100,000), men 39.0 6.7 vs 41.6 9.1 (p 0.001) Age-adjusted mortality (100,000), women 13.7 3.8 vs 14.3 4.6 (p 0.11) Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia (lung) Men 168 3.1 (2.6–3.5) Women 40 0.4 (0.3–0.6) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up— incidence (lung) Zones A, B—men 57 1.3 (1.0–1.7) women 4 0.6 (0.2–1.7) Bertazzi et al., 1998 Seveso residents—15-year follow-up— incidence (lung) Zone A—men 4 1.0 (0.4–2.6) Zone B—men 34 1.2 (0.9–1.7) women 2 0.6 (0.1–2.3) Zone R—men 176 0.9 (0.8–1.1) women 29 1.0 (0.7–1.6) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up— incidence (lung) Zone A—men 4 1.0 (0.3–2.5) Zone B—men 34 1.2 (0.9–1.7) women 2 0.6 (0.1–2.1) Zone R—men 176 0.9 (0.8–1.0) women 29 1.0 (0.7–1.5) Svensson et al., 1995 Swedish fishermen East coast (lung and larynx) 16 0.8 (0.5–1.3) West coast (lung and larynx) 77 0.9 (0.7–1.1) continued

336 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in VAO Bertazzi et al., 1993 Seveso residents—10-year follow-up— incidence (trachea, bronchus, lung) Zone A—men 2 0.8 (0.2–3.4) Zone B—men 18 1.1 (0.7–1.8) Zone R—men 96 0.8 (0.7–1.0) women 16 1.5 (0.8–2.5) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 576 1.2 (1.1–1.3) Branch of Service Navy 141 1.4 (1.2–1.7) Army 372 1.2 (1.1–1.3) Air Force 63 1.0 (0.7–1.2) Histologic type Adenocarcinoma 188 1.5 (1.2–1.7) Squamous 152 1.2 (1.0–1.4) Small-cell 87 1.2 (0.97–1.5) Large-cell 79 1.1 (0.8–1.3) Other 70 1.1 (0.8–1.3) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 544 1.2 (1.1–1.3) Branch of service Navy 135 1.4 (1.2–1.6) Army 339 1.1 (1.0–1.6) Air Force 71 1.1 (0.9–1.4) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs non-deployed Incidence (1982–2000) 78 2.4 (1.6–3.5) Histologic type Adenocarcinoma 27 2.7 (1.3–5.6) Squamous 19 5.0 (1.8–17.0) Small-cell 14 2.1 (0.9–5.5) Large-cell 8 1.1 (0.4–3.3) Other 10 1.8 (0.6–5.5) Mortality (1966–2001) 67 1.8 (1.2–2.7)

CANCER 337 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Pavuk et al., 2005 White Air Force comparison subjects only (respiratory system)—incidence Serum TCDD levels (pg/g), based on model with exposure variable loge(TCDD)d Per unit increase of –loge(TCDD) in pg/g 36 1.7 (0.9–3.2) Quartiles (pg/g) 0.4–2.6 6 1.0 2.6–3.8 8 1.1 (0.3–3.4) 3.8–5.2 9 1.2 (0.4–3.5) 5.2 13 1.9 (0.7–5.5) Number of years served in Southeast Asia (SEA) Per year of service 36 1.1 (0.9–1.2) Quartiles (years in SEA) 0.8–1.3 8 1.0 1.3–2.1 4 0.5 (0.2–1.8) 2.1–3.7 11 0.7 (0.3–2.0) 3.7–16.4 13 0.7 (0.3–2.0) Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort (trachea, bronchus, lung) 41 1.0 (0.6–1.5) Low pay grade at time of discharge * 1.6 (0.9–3.0) High pay grade at time of discharge * 0.8 (0.6–1.1) Studies Reviewed in Update 2004 Akhtar et al., 2004 White AFHS subjects vs national rates (respiratory system) Ranch Hand veterans Mortality—all 21 0.9 (0.6–1.3) Incidence—all 33 1.1 (0.8–1.6) With tours between 1966–1970 26 1.1 (0.7–1.6) Comparison veterans Mortality—all 38 1.1 (0.8–1.5) Incidence—all 48 1.2 (0.9–1.6) With tours between 1966–1970 37 1.2 (0.9–1.6) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans (lung and bronchus) 10 3.7(0.8–17.1) AIHW, 1999 Australian Vietnam veterans—Validation 65 expected study (lung) 46e (49–81) CDVA, 1998a 65 expected Australian Vietnam veterans (lung) 120 (49–89) Studies Reviewed in Update 1998 CDVA, 1997a Australian Vietnam veterans (lung) 212 1.3 (1.1–1.4) CDVA, 1997b Australian National Service Vietnam veterans (lung) 27 2.2 (1.1–4.3) continued

338 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-14 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Dalager and Kang, Army Chemical Corps veterans (respiratory 1997 system) 11 1.4 (0.4–5.4) Mahan et al., 1997 Case–control of Vietnam-era Vietnam veterans—incidence (lung) 134 1.4 (1.0–2.0) Watanabe and Kang, US Army and Marine Corps Vietnam 1996 veterans (lung) Army Vietnam service 1,139 1.1* (p 0.05) Non-Vietnam 1,141 1.1* (p 0.05) Marine Vietnam service 215 1.2 (1.0–1.3) Non-Vietnam 77 0.9* Watanabe and Kang, Marine Vietnam service vs non-Vietnam 1995 (lung) 42 1.3 (0.8–2.1) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ADVA, Australian Department of Vet- eran Affairs; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; MCPA, methyl- 4-chlorophenoxyacetic acid; NS, not significant; PCDD, polychlorinated dibenzodioxin; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d The original paper implied that the exposure metric for TCDD was based on actual measured serum levels of TCDD. Subsequent correspondence between the Committee and the investigators indicated that the metric was actually transformed using the natural logarithm of TCDD. e Self-reported medical history. Answer to question: “Since your first day of service in Vietnam, have you been told by a doctor that you have lung cancer?” * Information not provided by study authors. Studies in italics have been superseded by newer studies of the same cohorts. Publications arising from the US AHS have provided findings on the risk of lung cancer in farmers (private pesticide applicators), their spouses, and commer- cial pesticide applicators, but no results peculiar to any of the herbicides under consideration here have been published. Blair et al. (2005a) reported that farmers and their spouses both had mortality from lung cancer substantially lower than the general population of Iowa and North Carolina, with rate ratios of around 0.4 (see Table 6-14). Such low mortality may have been due to chance, the healthy-worker effect, lower consumption of tobacco, increased level of exercise, or the protec- tive effect of endotoxins to which many agricultural workers may be exposed. In a publication on the incidence of lung cancer through 2001, Alavanja et al. (2004) stated, without giving quantitative results, that the farmers had a markedly lower incidence of lung cancer than the general populations of their states, which

CANCER 339 might be largely attributable to low rates of smoking; 2,4-D was not among the chemicals for which specific rate ratios were provided, although it was implicit that 2,4-D exposure had been analyzed for any association with the occurrence of lung cancer. A later publication on cancer incidence from recruitment through 2002 (Alavanja et al., 2005) presented findings on subgroups (farmers, their spouses, and commercial applicators; see Table 6-14), none of which showed an increased risk of lung cancer. In a cohort study in New Zealand, ’t Mannetje et al. (2005) found that mortality from cancer of the trachea, bronchus, or lung (ICD-9 162) showed a non-significant excess (SMR 1.4, 95% CI 0.7–2.4) in phenoxy herbicide pro- ducers, who also had potential exposure to dioxins. Among phenoxy herbicide sprayers, however, the estimated risk was lower than expected (SMR 0.5, 95% CI 0.2–1.1). Torchio et al. (1994) reported on the mortality experience of a cohort of 23,401 male farmers in the Piedmont area of Italy from the time when they reg- istered to use agricultural pesticides (1970–1974) through 1986. The provinces in that area are characterized by higher use of herbicides, particularly 2,4-D and MCPA, than the rest of the country. The estimated risk of lung cancer was significantly reduced (155 cases; SMR 0.45, 95% CI 0.38–0.52). The authors suggested that the relatively short duration of follow-up and the healthy-worker effect contributed to the observation of reduced mortality. Reif et al. (1989) performed a series of case–control analyses on the sample of 19,904 people with specified occupations among the 24,762 men 20 years old or older entered from 1980 to 1984 into the the New Zealand Cancer Registry. The focus of their study was on the 134 for whom forestry work was the most recent occupation listed. For each type of cancer, the registrants with any other type of cancer were used as controls. Of 4,224 people with lung cancer, 30 had most recently been forestry workers (OR 1.27, 95% CI 0.84–1.91). Environmental Studies No new environmental studies concerning exposure to the compounds of interest and respiratory cancer were published since Update 2004. Vietnam-Veteran Studies In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) did not find any excess risk of mortality from lung cancer in the entire cohort (CRR 0.94, 95% CI 0.62–1.48) but did observe an association in veterans who were classified as having a low pay grade at the time of discharge (RR 1.64, 95% CI 0.94–2.89). When the first findings of the study (Boyle et al., 1987) were considered in VAO, mortality had been too low to support any conclusions. Pavuk et al. (2005) analyzed the incidences of several types of cancer in

340 VETERANS AND AGENT ORANGE: UPDATE 2006 subjects in the comparison group in the AFHS in 1982–2003 in terms of their serum TCDD concentrations and the number of years served in Southeast Asia. Their work extends to people with lower TCDD exposures the analyses of can- cer incidences observed in the Ranch Hand subjects themselves (Akhtar et al., 2004), which were considered in Update 2004. In those analyses, cancers of the lung were included with other cancers of the “respiratory system.” There was a non-significant increase in the incidence of cancer of the respiratory tract with increased serum TCDD (RR 1.7 per unit increase in loge[TCDD concentration in picograms per gram], 95% CI 0.9–3.2). However, there was no evidence of an association between the number of years of service in Southeast Asia and the incidence of respiratory cancer (see Table 6-14 for a comparison of the risks estimated for the quartiles of TCDD concentrations with the number of years served in Southeast Asia). The recent update of the health experience of Australian Vietnam veterans showed significant associations with the incidence of lung cancer (SIR 1.23, 95% CI 1.13–1.33) (ADVA, 2005a) and mortality (SMR 1.18, 95% CI 1.08– 1.28) (ADVA, 2005b) when all Vietnam veterans (all male, all branches, “defence forces,” and “Citizen Military Forces”) were compared with the general popula- tion of Australia. When conscripted male Army veterans deployed to Vietnam (National Service veterans) were compared with their non-deployed counterparts (National Service non-veterans), the increase in the incidence of lung cancer was more pronounced (SIR 2.35, 95% CI 1.60–3.49) (ADVA, 2005c). The lat- ter analysis makes use of the presumably more comparable reference group of other veterans and may account for the underestimation of rate ratios obtained when the general population is used (the healthy-warrior effect). There was some variation in rate ratios with branch of service for both incidence of lung cancer (ADVA, 2005a) and mortality from it (ADVA, 2005b); increases were most pro- nounced in the Navy, substantial in the Army, and equivocal in the Air Force (see Table 6-14). Rate ratios of some histologic subtypes, especially adenocarcinomas and squamous-cell carcinomas, were higher. Biologic Plausibility As noted in previous VAO reports, there is evidence of increased incidence of squamous-cell carcinoma of the lung in male and female rats exposed to TCDD at high concentrations (Kociba et al., 1978; Van Miller et al., 1977). A more recent study reported a significant increase in cystic keratinizing epitheliomas in female rats exposed to TCDD for 2 years (NTP, 2006), and increases in the incidences of bronchiolar metaplasia, acinar vacuolization, and inflammation were observed in the high-dose (100-ng/kg) group. A recent 2-year study of F344 rats exposed to cacodylic acid at 0–100 ppm and B6C3F1 mice exposed at 0–500 ppm failed to detect neoplasms in the lung at any dose (Arnold et al., 2006); this finding is consistent with that of previous studies. However, exposure to cacodylic acid has previously been shown to in-

CANCER 341 crease tumor multiplicity in mouse strains susceptible to developing lung tumors (for example, A/J strain; Hayashi et al., 1998) or mice pretreated with an intitiat- ing agent (4-nitroquinoline 1-oxide; Yamanaka et al., 1996). The data indicate that cacodylic acid may act as a tumor promoter in the lung. The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis The evidence remains inconclusive but suggestive of an association between exposure to at least one compound of interest and the risk of developing or dying from lung cancer. The best evidence comes from studies of heavily exposed occu- pational cohorts. The latest findings from the US AFHS suggest an increase in risk with concentration of serum TCDD even in the subjects who made up the comparison group, whose TCDD exposure was considerably lower than that of the main Ranch Hand group. The American and Australian cohort studies of Viet- nam veterans, which presumably cover a large proportion of exposed soldiers, show higher than expected incidence of and mortality from lung cancer. The main limitations of those studies are that there was no assessment of exposure, as there was in, for example, the Ranch Hand study, and that some potential confound- ing variables, notably smoking, could not be accounted for. It is unlikely that the distribution of smoking would differ greatly between veteran cohorts, so the likelihood of important confounding by smoking is probably low. Those studies therefore lend support to the findings of the Ranch Hand study. The method- ologically sound US AHS did not show any increased risks of lung cancer, but, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of these contemporary farmers was probably negligible. The evi- dence from occupational studies remains inconsistent; for example, in the study by Bodner et al. (2003), no excess risks of lung cancer in chemical-company employees were found, but these results must be weighed against results in pre- viously reviewed occupational cohorts that did show evidence of an association (Becher et al., 1996; Ott and Zober, 1996; Steenland et al., 1999). Also supportive of an association are the numerous lines of mechanistic evidence, discussed in the section on biologic plausibility, which provide fur- ther support for the conclusion that the evidence of an association is limited or suggestive. Conclusion On the basis of its evaluation of the 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 carcinomas of the lung, bronchus, and trachea.

342 VETERANS AND AGENT ORANGE: UPDATE 2006 BONE AND JOINT CANCER ACS (2006) estimated that about 1,500 men and 1,260 women would re- ceive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2006 and that 730 men and 530 women would die from these cancers. Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 6-15. Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (50–64 years). Among the risk factors for adults’ contracting of bone or joint cancer are exposure to ionizing radiation in treatment for other cancers and a history of some non-cancer bone diseases, including Paget’s disease. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and bone and joint cancer. Additional in- formation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-16 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies In New Zealand, ’t Mannetje et al. (2005) followed the mortality experience of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers from 1969 and 1973, respectively, through 2000. No deaths from bone and joint cancer (ICD-9 170) were observed in either the producer or sprayer group. TABLE 6-15 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Men 0.9 0.9 0.7 1.1 1.2 1.1 1.4 1.5 1.0 Women 0.9 1.0 0.4 0.9 1.1 0.3 1.0 1.0 0.4 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

CANCER 343 TABLE 6-16 Selected Epidemiologic Studies—Bone and Joint Cancer Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies Merletti et al., 2006 Association of occupational exposure and risk 18 2.6 (1.5–4.6) of bone sarcoma ’t Mannetje et al., Phenoxy herbicide producers and sprayers 0 — 2005 (men and women) Torchio et al., 1994 Italian licensed pesticide users 10 0.8 (0.4–1.4) Reif et al., 1989 New Zealand forestry workers—nested 1 1.7 (0.2–13.3) case–control (incidence) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licenced herbicide applicators 0 — Studies Reviewed in Update 2000 Rix et al., 1998 Danish paper mill workers—incidence Men 1 0.5 (0.0–2.7) Women 0 — Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 1 0.5 (0.0–2.6) Hertzman et al., 1997 British Columbia sawmill workers Mortality 5 1.3 (0.5–2.7) Incidence 4 1.1 (0.4–2.4) Kogevinas et al., 1997 IARC cohort (men and women) 5 1.2 (0.4–2.8) Workers exposed to any phenoxy herbicide 5 1.2 (0.4–2.7) or chlorophenol Exposed to TCDD (or higher-chlorinated 3 1.1 (0.2–3.1) dioxins) Not exposed to TCDD (or higher- 2 1.4 (0.2–5.2) chlorinated dioxins) Ramlow et al., 1996 Dow pentachlorophenol production workers 0 * (included in the IARC cohort and the NIOSH Dioxin Registry) 0-year latency 0 — 15-year latency 0 — Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 49 1.3 (1.0–1.8) White women 1 1.2 (0.0–6.6) Collins et al., 1993 Monsanto Company workers (included in the 2 5.0 (0.6–18.1) NIOSH cohort) Studies Reviewed in VAO Ronco et al., 1992 Danish and Italian farm workers Male Danish farmers 9 0.9* Female Danish farmers 0 * Fingerhut et al., 1991 NIOSH—entire cohort 2 2.3 (0.3–8.2) 1-year exposure, 20-year latency 1 5.5 (0.1–29.0) Zober et al., 1990 BASF employees—basic cohort 0 0 (0.0–65.5) continued

344 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-16 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Bond et al., 1988 Dow 2,4-D production workers (included in the 0 — (0.0–31.1) IARC cohort and the NIOSH Dioxin Registry) Coggon et al., 1986 British MCPA production workers (included in 1 0.9 (0.0–5.0) the IARC cohort) Wiklund, 1983 Swedish male and female agricultural 44 1.0 (0.6–1.4)d workers—incidence Burmeister, 1981 Iowa farmers 56 1.1 (NS) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia Mortality standardized to Samara Region (bone, soft-tissue cancer) Men 7 2.1 (0.9–4.4) Women 7 1.4 (0.6–3.0) Studies Reviewed in Update 2000 Bertazzi et al., 1998 Seveso residents—15-year follow-up Zone B—women 1 2.6 (0.3–19.4) Zone R—men 2 0.5 (0.1–2.0) women 7 2.4 (1.0–5.7) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up Zone B—women 1 2.6 (0.0–14.4) Zone R—men 2 0.5 (0.1–1.7) women 7 2.4 (1.0–4.9) VIETNAM VETERANS Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 4 0.9 (0.1–11.3) AFHS, 1996 Air Force Ranch Hand veterans 0 * Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 27 0.8 (0.4–1.7) Marine Vietnam veterans 11 1.4 (0.1–21.5) Anderson et al., 1986b Wisconsin Vietnam veterans 1 * Lawrence et al., 1985 New York Vietnam veterans 8 1.0 (0.3–3.0) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; CI, con- fidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophen- oxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d 99% CI. * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohorts.

CANCER 345 Merletti et al. (2006) reported results from a multicenter case–control study conducted in seven European countries in 1995–1997 and focused on rare cancers, including bone sarcomas. A total of 96 cases were identified, and controls were selected in at least a 1:4 ratio and matched on the basis of age group, sex, and region. Exposure was determined indirectly solely on the basis of self-reported job titles. Although risk was significantly increased in those who reported use of pesticides, insecticides, or herbicides, no data are given with respect to the specific compounds of interest to this report. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re- ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of bone cancer was reduced (10 cases; SMR 0.75, 95% CI 0.36–1.38). Starting with the 19,904 men entered into the the New Zealand Cancer Reg- istry from 1980–1984 with a specified occupation, Reif et al. (1989) contrasted the 49 cases of bone cancer with the remaining subjects having other types of cancer. Of the 134 cancer registrants for whom forestry worker (with presumed exposure to phenoxy herbicides and chlorophenols) was the most recent occupa- tion, the proportion with bone cancer (1 case; OR 1.72, 95% CI 0.22–13.30) was not significantly elevated. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and bone and joint cancer were published since Update 2004. Vietnam-Veteran Studies The AFHS completed the report on its scheduled 2002 follow-up examina- tion of participants. The examination included questionnaires, physical examina- tions, and clinical assessments, all of which were used to ascertain bone-cancer risk in participants. Too few events were observed in the cohort to allow assess- ment of the risk. The Third Australian Vietnam Veterans Mortality Study 2005 assessed mor- tality in Australian Vietnam veterans in all branches of service. Mortality ex- perience (through 2001) in the veterans was compared with that in the general population of Australia. However, too few cases of bone cancer were observed in the cohort to allow assessment of RR. Biologic Plausibility No animal studies reported an increased incidence of bone and joint cancers after exposure to the compounds of interest. The biologic plausibility of the car- cinogenicity of the compounds of interest in general is summarized at the end of this chapter.

346 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis Results of several pertinent studies have been published since the previous update and were noted above. The studies either reported a non-significant in- crease in risk of bone and joint cancer, observed too few events to estimate RR adequately, or did not present data that sufficiently linked observed results to specific compounds of interest to this report. Thus, the new results add little to the previous body of results, summarized in Table 6-16, that taken together do not indicate an association between exposure to the compounds of interest and bone cancer. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and bone cancer. That conclusion is based on occupational and environmental studies in which subjects were exposed to a variety of herbi- cides and herbicide mixtures. SOFT-TISSUE SARCOMAS Soft-tissue sarcoma (STS) (ICD-9 164.1, 171) arises in soft somatic tis- sues within and between organs. Three of the most common types of STS— liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that in 2006 about 5,720 men and 3,810 women would receive diagnoses of STS in the United States and that about 1,830 men and 1,670 women would die from it (ACS, 2006). The average annual incidence of STS is shown in Table 6-17. TABLE 6-17 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in United States a 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Men 4.2 4.3 4.3 5.0 4.9 6.7 6.7 7.3 3.5 Women 2.9 3.1 3.1 4.2 4.0 7.1 5.1 4.8 7.7 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

CANCER 347 Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers and some inherited conditions, including Gardner’s syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have been identified as possible risk factors (Zahm and Fraumeni, 1997). Conclusions from VAO and Updates The committee responsible for VAO judged that the strong findings in the IARC and NIOSH cohorts, plus extensive Scandinavian case–control studies, complemented by consistency in preliminary reports on the Seveso population and one statistically significant finding in a state study of Vietnam veterans, con- stituted sufficient information to determine that there is an association between exposure to at least one of the compounds of interest and STS. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-18 summarizes the relevant studies. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. Mortality rates for soft-tissue sarcoma stan- dardized with the national rates of the 11 contributing countries did not indicate any association to nonvolatile organochlorine compounds, including TCDD (ever exposed: 4 cases, SMR 0.80, 95% CI 0.22–2.04; never exposed: 8 cases, SMR 1.22, 95% CI 0.53–2.41) as derived using a JEM approach. In New Zealand, ’t Mannetje et al. (2005) followed the mortality experience of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers from 1969 and 1973, respectively, through 2000. A single death from STS (ICD-9 171) was observed (0.23 expected) in the sprayer group. In a prospective cohort study of private pesticide applicators, commercial applicators, and spouses of the private applicators, Alavanja et al. (2005) reported 10 and 3 incident cases of “soft tissue” cancer in the private applicators (SIR 0.65, 95% CI 0.31–1.20) and their spouses (SIR 0.48, 95% CI 0.10–1.41), respectively, and none among the commercial applicators; those results led to non-significant risk estimates below the null. In a study of cancer mortality in the same prospective cohort, Blair et al. (2005a) reported four and three deaths from “soft tissue” cancer in the pesticide applicators (SMR 0.7, 95% CI 0.2–1.8) and their spouses (SMR 1.4, 95% CI 0.3–4.1), respectively. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re-

348 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-18 Selected Epidemiologic Studies—Soft-Tissue Sarcoma Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c OCCUPATIONAL New Studies McLean et al., 2006 IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine compounds Never 8 1.2 (0.5–2.4) Ever 4 0.8 (0.2–2.0) Alavanja et al., 2005 US Agriculture Health Study—incidence Private applicators (men and women) 10 0.7 (0.3–1.2) Spouses of private applicators ( 99% women) 3 0.5 (0.1–1.4) Commercial applicators (men and women) — 0.0 (0–3.8) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) 4 0.7 (0.2–1.8) Spouses of private applicators ( 99% women) 3 1.4 (0.3–4.1) ’t Mannetje et al., Phenoxy herbicide producers (men and 2005 women) 0 0.0 (0.0–19.3) Phenoxy herbicide sprayers ( 99% men) 1 4.3 (0.1–23.8) Torchio et al., 1994 Italian licensed pesticide users 2 1.0 (0.1–3.5) Reif et al., 1989 New Zealand forestry workers—nested case–control (incidence) 4 3.2 (1.2–9.0) Studies Reviewed in Update 2004 Bodner et al., 2003 Dow chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 2 2.4 (0.3–8.6) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0 * Hooiveld et al., 1998 Dutch chemical production workers (included in the IARC cohort) 0 * Rix et al., 1998 Danish paper mill workers—incidence Women employed in sorting and packing 8 4.0 (1.7–7.8) Men employed in sorting and packing 12 1.2 (0.6–2.0) Studies Reviewed in Update 1998 Hertzman et al., 1997 Canadian sawmill workers 11 1.0 (0.6–1.7) Kogevinas et al., 1997 IARC cohort (men and women) Workers exposed to any phenoxy herbicide or chlorophenol 9 2.0 (0.9–3.8) Exposed to TCDD (or higher- chlorinated dioxins) 6 2.0 (0.8–4.4) Not exposed to TCDD (or higher- chlorinated dioxins) 2 1.4 (0.2–4.9)

CANCER 349 TABLE 6-18 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Ott and Zober, 1996 BASF employees—incidence 0 0.2 expected Ramlow et al., 1996 Dow pentachlorophenol production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0 0.2 expected Studies Reviewed in Update 1996 Kogevinas et al., 1995 IARC cohort—incidence (men and women) 11 * Mack, 1995 US cancer registry data (SEER program) review Men 3,526 * Women 2,886 * Blair et al., 1993 US farmers in 23 states 98 0.9 (0.8–1.1) Lynge, 1993 Danish production workers—updated incidence for men and women (included in the IARC cohort) 5 2.0 (0.7–4.8) Kogevinas et al., 1992 IARC cohort (men and women) 10–19 years since first exposure 4 6.1 (1.7–15.5) Studies Reviewed in VAO Bueno de Mesquita Dutch phenoxy herbicide workers (included et al., 1993 in the IARC cohort) 0 0.0 (0.0–23.1) Hansen et al., 1992 Danish gardeners—incidence (men and women) Male gardeners 3 5.3 (1.1–15.4) Smith and Australia residents 30 1.0 (0.3–3.1) Christophers, 1992 Fingerhut et al., 1991 NIOSH cohort—entire cohort 4 3.4 (0.9–8.7) 1-year exposure, 20-year latency 3 9.2 (1.9–27.0) Manz et al., 1991 German production workers—men and women (included in the IARC cohort) 0 * Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) 4 2.0 (0.6–5.2) Zober et al., 1990 BASF employees—basic cohort 0 * Alavanja et al., 1989 USDA forest and soil conservationists 2 1.0 (0.1–3.6) Bond et al., 1988 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) 0 * Wiklund et al., 1988, Swedish agricultural workers (men and 1989b women) 7 0.9 (0.4–1.9) Woods et al., 1987 Washington State residents—incidence High phenoxy exposure * 0.9 (0.4–1.9) Self-reported chloracne * 3.3 (0.8–14.0) Coggon et al., 1986 British MCPA chemical workers (included in the IARC cohort) 1 1.1 (0.03–5.9) Hoar et al., 1986 Kansas residents—incidence All farmers 95 1.0 (0.7–1.6) Farm use of herbicides 22 0.9 (0.5–1.6) continued

350 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-18 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Smith and Pearce, Reanalysis of New Zealand workers 133 1.1 (0.7–1.8)d 1986 Vineis et al., 1986 Italian rice growers Among all living women 5 2.4 (0.4–16.1) Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) Men 5 2.7 (0.9–6.3) Women 0 * Balarajan and Agricultural workers in England Acheson, 1984 Overall 42 1.7 (1.0–2.9) Those under 75 years old 33 1.4 (0.8–2.6) Smith et al., 1984 Update of New Zealand workers 17 1.6 (0.7–3.8)d Blair et al., 1983 Florida pesticide applicators 0 * Smith et al., 1983 New Zealand workers exposed to herbicides 17 1.6 (0.8–3.2)d Hardell, 1981 Swedish residents Exposed to phenoxy acids 13 5.5 (2.2–13.8) Exposed to chlorophenols 6 5.4 (1.3–22.5) Eriksson et al., 1979, Swedish workers 25 (2.5–10.4) 1981 5:1 matched ENVIRONMENTAL New Studies Pahwa et al., 2006 Any phenoxy herbicide 46 1.10 (0.7–1.5) 2,4-D 41 0.96 (0.6–1.5) Mecoprop 12 0.98 (0.5–1.9) MCPA 12 1.08 (0.5–2.2) Studies Reviewed in Update 2004 Tuomisto et al., 2004 Finnish STS patients and controls 110 Quintile 2 (median tissue concentration 20 ng/kg WHO-TEQ) * 0.4 (0.2–1.1) Quintile 5 (median tissue concentration ~60 ng/kg WHO-TEQ) * 0.7 (0.2–2.0) Comba et al., 2003 Residents near an industrial-waste incinerator in Mantua, Italy—incidence Residence within 2 km of incinerator 5 31.4 (5.6–176.1) Studies Reviewed in Update 2002 Costani et al., 2000 Residents near a chemical plant in Mantua, Italy—incidence 20 2.3 (1.3–3.5) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso—20-year follow-up (men and women) 0 * Viel et al., 2000 Residents near a French solid-waste incinerator—incidence Spatial cluster 45 1.4 (p 0.004) 1994–1995 12 3.4 (p 0.008) Bertazzi et al., 1998 Seveso—15-year follow-up (men and women) Zone R—men 4 2.1 (0.7–6.5)

CANCER 351 TABLE 6-18 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up (men and women) Zone R—men 4 2.1 (0.6–5.4) Gambini et al., 1997 Italian rice growers 1 4.0 (0.1–22.3) Svensson et al., 1995 Swedish fishermen—incidence (men and women) West coast 3 0.5 (0.1–1.4) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—morbidity Zone R—men 6 2.8 (1.0–7.3) women 2 1.6 (0.3–7.4) Studies Reviewed in VAO Lampi et al., 1992 Finnish community exposed to chlorophenol contamination (men and women) 6 1.6 (0.7–3.5) Bertazzi et al., 1989a Seveso residents—10-year follow-up Zone A, B, R—men 2 5.4 (0.8–38.6) women 1 2.0 (0.2–1.9) Bertazzi et al., 1989b Seveso residents—10-year follow-up Zone R—men 2 6.3 (0.9–45.0) Zone B—women 1 17.0 (1.8–163.6) VIETNAM VETERANS New Studies ADVA, 2005a Australian Vietnam veterans vs Australian population—incidence 35 1.0 (0.7–1.3) Navy 6 0.8 (0.3–1.7) Army 29 1.2 (0.8–1.6) Air Force 0 0.0 (0.0–1.1) ADVA, 2005b Australian Vietnam veterans vs Australian population—mortality 12 0.8 (0.4–1.3) Navy 3 0.9 (0.2–2.4) Army 9 0.8 (0.4–1.5) Air Force 0 0.0 (0.0–2.3) ADVA, 2005c Australian men conscripted Army National Service Vietnam-era veterans—deployed vs non-deployed Incidence 10 1.0 (0.4–2.4) Mortality 3 0.5 (0.1–2.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.8 (0.1–12.8) AIHW, 1999 Male Australian Vietnam veterans 14 27 expected (17–37) CDVA, 1998a Male Australian Vietnam veterans 398e 27 expected (17–37) continued

352 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-18 Continued Estimated Exposed Relative Risk Reference Study Populationa,b Casesc (95% CI)c CDVA, 1998b Female Australian Vietnam veterans 2e 0 expected (0–4) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 9 1.0 (0.4–1.8) CDVA, 1997b Australian National Service Vietnam veterans 2 0.7 (0.6–4.5) Clapp, 1997 Massachusetts Vietnam Veterans 18 1.6 (0.5–5.4) AFHS, 1996 Ranch Hand veterans 0 * Watanabe and Kang, US Marines in Vietnam 0 * 1995 Studies Reviewed in Update 1996 Visintainer et al., Michigan Vietnam veterans 8 1.1 (0.5–2.2) 1995 Studies Reviewed in VAO Watanabe et al., 1991 Army Vietnam veterans 43 1.1 Marine Vietnam veterans 11 0.7 Bullman et al., 1990 Army I Corps Vietnam veterans 10 0.9 (0.4–1.6) Michalek et al., 1990 Ranch Hand veterans 1 * Comparisons 1 * Breslin et al., 1988 Army Vietnam veterans 30 1.0 (0.8–1.2) Marine Vietnam veterans 8 0.7 (0.4–1.3) Kogan and Clapp, Vietnam veterans in Massachusetts 9 5.2 (2.4–11.1) 1988 Fett et al., 1987 Australian Vietnam veterans 1 1.3 (0.1–20.0) Anderson et al., 1986b Wisconsin Vietnam veterans 4 * Breslin et al., 1986 US Vietnam veterans Army 30 1.0* Marines 8 0.7* Kang et al., 1986 Vietnam veterans vs. Vietnam-era veterans 86 0.8 (0.6–1.1) Lawrence et al., 1985 New York State Vietnam veterans 2 1.1 (0.2–6.7) Greenwald et al., New York State Vietnam veterans 10 0.5 (0.2–1.3) 1984 ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ADVA, Australian Department of Veteran Affairs; 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, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; SEER, Surveillance, Epidemiology, and End Results Program; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; WHO-TEQ, toxicity equivalency as defined by the World Health Organization. a Table shows mortality unless otherwise noted. b Cohorts are male unless otherwise noted. c Given when available. d 90% CI. e Self-reported medical history. Answer to question: “Since your first day of service in Vietnam, have you been told by a doctor that you have soft-tissue sarcoma?” * Information not provided by study authors. — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohorts.

CANCER 353 ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of cancer of the connective soft tissue was not increased (two cases; SMR 0.95, 95% CI 0.11–3.45). Reif et al. (1989) performed a series of case–control analyses on the sample of 19,904 people with specified occupations among the 24,762 men 20 years old or older entered into the the New Zealand Cancer Registry in 1980–1984. The focus of their study was on the 134 for whom forestry work was the most recent occupation listed. For each type of cancer, the people with any other type of can- cer were used as controls. Of 142 people with STS, four had most recently been forestry workers (OR 3.24, 95% CI 1.17–8.98). Environmental Studies In the case–control study of men living in six Canadian provinces, Pahwa et al. (2006) investigated whether exposure to phenoxy herbicides and other pesticides was associated with the incidence of STS. (The results of the study in terms of farm work or residence were reported in Pahwa et al. [2003], which has not been previously reviewed in this series, but the current citation more specifi- cally addresses the VAO charge.) Interviews were completed with 357 men who received new diagnoses of STS in 1991–1994 and with 1,506 control subjects. No associations were found with any exposures to phenoxy herbicides (OR 1.07, 95% CI 0.80–1.44), to 2,4-D (OR 0.97, 95% CI 0.71–1.32), to mecoprop (2-[2-methyl-4-chlorophenoxy]propanoic acid) (OR 1.40, 95% CI 0.86–2.25), or to MCPA (OR 1.05, 95% CI 0.54–2.02). Vietnam-Veteran Studies In a set of three reports updating the health status of Australian Vietnam veterans, no associations between Vietnam service and cancers of connective soft tissue were found in comparing veterans with the general population of Austra- lia in incidence (SIR 0.99, 95% CI 0.66–1.31) (ADVA, 2005a) and mortality (SMR 0.75, 95% CI 0.38–1.28) (ADVA, 2005b). When conscripted male Army veterans deployed to Vietnam (National Service veterans) were compared with their non-deployed counterparts (National Service non-veterans), no increases were found in the incidence of STS (SIR 0.99, 95% CI 0.39–2.44) or mortality from it (SMR 0.48, 95% CI 0.08–2.01) (ADVA, 2005c). Biologic Plausibility In a 2 year study, dermal application of TCDD to Swiss-Webster mice led to an increase in fibrosarcomas in the female mice, but not male mice (NTP, 1982b). There is some concern that the increase in fibrosarcomas may be associated with the treatment protocol, rather than due to the treatment with TCDD. The NTP gavage study (1982a) also found elevated incidences of fibrosarcomas in male

354 VETERANS AND AGENT ORANGE: UPDATE 2006 and female rats and in female mice (as VAO also reported; but Update 2004 said there were no animal data specifically supporting STS). The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis Previous committees have concluded that the occupational, environmen- tal, and Vietnam-veteran studies showed sufficient evidence to link herbicide exposure to STS. Three new studies did not find associations with STS, but the statistical power to detect excess risks in these small cohorts of phenoxy herbi- cide producers and sprayers was low; furthermore, the populations in the United States, Canada, and Italy were exposed to contemporary phenoxy herbicides unlikely to contain TCDD. The findings of a sizable multinational investigation of paper and pulp workers were indeterminant for the rather nonspecific exposure “nonvolatile organochlorines,” but an occupational analysis of those entered into the New Zealand Cancer Registry in the early 1980s did find a strong association between STS and having been a forestry worker. The studies of Australian vet- erans did not show any evidence of increased risks among deployed soldiers, but the power to detect excess risk was low and there were no data regarding actual exposures. The committee did not find that these new data justified modifying the previous conclusion. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an asso- ciation between exposure to at least one of the compounds of interest and STS. SKIN CANCER—MELANOMA Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma, or simply melanoma) and neoplasms that do not. Non-melanoma skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 6-19. The committee responsible for Update 1998 first chose to address melanoma studies separately from those of non-melanoma skin cancer. Some researchers report results by combining all types of skin cancer without specifying type. The present committee believes that such information is not interpretable (although there is a supposition that mortality figures refer predominantly to melanoma and sizable incidence figures refer to non-melanoma skin cancer). Therefore, the committee is interpreting data

CANCER 355 TABLE 6-19 Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal- and Squamous-Cell Cancers) in United States a 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age Melanomas All All All of the Skin Races White Black Races White Black Races White Black Men 32.4 38.6 0.5 45.4 52.7 1.1 55.4 64.8 3.5 Women 24.6 30.0 0.2 26.9 32.2 1.8 28.6 34.6 1.2 SEER incidence data are not available for non-melanoma skin cancer. a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003. only on results that are specified as applying to melanoma or to non-melanoma skin cancer. ACS estimated that about 34,260 men and 27,930 women would receive diagnoses of cutaneous melanoma (ICD-9 172) in the United States in 2006 and 5,020 men and 2,890 women would die from it (Jemal et al., 2006). More than a million cases of non-melanoma skin cancer (ICD-9 173), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2006); it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. ACS reports that although melanoma accounts for only about 4 percent of skin-cancer cases, it is responsible for about 79 percent of skin-cancer deaths (2006). It estimates that 1,000–2,000 people die each year from non-melanoma skin cancer. Melanoma occurs more frequently in fair-skinned people than in dark-skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks. The incidence increases with age, although more strikingly in men than in women. Other risk factors include the presence of certain moles on the skin, suppression of the immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun exposure patterns. Excessive exposure to UV radiation is the most important risk factor for non-melanoma skin cancer, although some skin diseases and chemical exposures have also been identified as potential risk factors. Exposure to inorganic arsenic is a risk factor for skin cancer (this does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can also be assumed to be a risk factor). Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between

356 VETERANS AND AGENT ORANGE: UPDATE 2006 exposure to the compounds of interest and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that con- clusion. The Update 1998 committee considered the literature on melanoma sepa- rately from that of non-melanoma skin cancer. It found that there was inadequate or insufficient information to determine whether there is an association between the compounds of interest and melanoma. The Update 2000, Update 2002, and Update 2004 committees concurred with the findings of the Update 1998 com- mittee. Table 6-20 summarizes the relevant melanoma studies. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational IARC cohort of 60,468 pulp and paper industry workers. A JEM was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine compounds (which would include TCDD). Death from melanoma was not more strongly associated with having ever been exposed to nonvolatile organochlorine compounds (n 21; SMR 1.17, 95% CI 0.72–1.78) than with having never been exposed (n 20; SMR 0.82, 95% CI 0.5–1.27). The study by ’t Mannetje et al. (2005) is an extension of a cohort study in New Zealand, which is part of an IARC international study of phenoxy herbicide producers and sprayers. Their report describes follow-up from 1969 to 2000 of 813 herbicide producers and 699 sprayers who were classified as exposed to dioxin and phenoxy herbicides. SMRs were computed relative to general New Zealand standards. No cases of melanoma were observed in the production workers, and only one in the sprayers; the estimated SMRs were therefore very unstable and had wide confidence intervals. In reporting on cancer incidence in the AHS cohort, Alavanja et al. (2005) found that the spouse group showed a significant excess of melanoma, with 67 observed cases (SIR 1.64, 95% CI 1.27–2.09). Such an excess was not seen in the private applicators (SIR 0.95, 95% CI 0.78–1.16) or the commercial ap- plicators (SIR 1.05, 95% CI 0.42–2.17). Melanoma was the only cancer type observed to have a significantly increased risk in the spouses. The authors consid- ered that result to be “unexpected” and commented that a high percentage of farm spouses engage in outdoor work that involves substantial exposure to sunlight. Blair et al. (2005a) studied mortality in the AHS cohorts of private applica- tors (mostly farmers) and their spouses. In the private applicators, there were 13 deaths from melanoma (SMR 0.7, 95% CI 0.4–1.3). In the spouses, there were two deaths from melanoma (SMR 0.4, 95% CI 0.1–1.6). The increase in mela- noma incidence observed among the AHS spouses is not yet reflected in mortality from melanoma, but the cohort has very low overall mortality compared with the

CANCER 357 TABLE 6-20 Selected Epidemiologic Studies—Melanoma Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL New Studies McLean et al., IARC cohort of pulp and paper workers 2006 Exposure to nonvolatile organochlorine compounds Never 20 0.8 (0.5–1.3) Ever 21 1.2 (0.7–1.8) Alavanja et al., US Agriculture Health Study—incidence 2005 Private applicators (men and women) 100 1.0 (0.8–1.2) Spouses of private applicators ( 99% women) 67 1.6 (1.3–2.1) Commercial applicators (men and women) 7 1.1 (0.4–2.2) Blair et al., 2005a US Agriculture Health Study Private applicators (men and women) 13 0.7 (0.4–1.3) Spouses of private applicators ( 99% women) 2 0.4 (0.1–1.6) ’t Mannetje et al., Phenoxy herbicide producers (men and women) 0 0.0 (0.0–3.0) 2005 Phenoxy herbicide sprayers ( 99% men) 1 0.6 (0.0–3.4) Torchio et al., Italian licensed pesticide users 9 1.2 (0.6–2.3) 1994 Magnani et al., UK case–control 1987 Herbicides * 1.2 (0.4–4.0) Chlorophenols * 0.9 (0.4–2.3) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators Melanoma, squamous-cell carcinoma, and unknown skin cancer (mortality presumably attributable to melanoma) 5 3.6 (1.2–8.3) Studies Reviewed in Update 2002 Thörn et al., 2000 Swedish lumberjack workers exposed to phenoxyacetic herbicides—incidence Women 1 3.5 (0.1–19.2) Men 0 — Studies Reviewed in Update 2000 Hooiveld et al., Dutch chemical production workers (included in 1998 the IARC cohort) 1 2.9 (0.1–15.9) Studies Reviewed in Update 1998 Hertzman et al., British Columbia sawmill workers 1997 Incidence 38 1.0 (0.7–1.3) Mortality 17 1.4 (0.9–2.0) Kogevinas et al., IARC cohort (men and women) 1997 Workers exposed to any phenoxy herbicide or chlorophenol 9 0.6 (0.3–1.2) Exposed to TCDD (or higher-chlorinated dioxins) 5 0.5 (0.2–3.2) Not exposed to TCDD (or higher- chlorinated dioxins) 4 1.0 (0.3–2.4) continued

358 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-20 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 244 1.0 (0.8–1.1) White women 5 1.1 (0.4–2.7) Lynge, 1993 Danish production workers—updated incidence (included in the IARC cohort) 4 4.3 (1.2–10.9) Studies Reviewed in VAO Ronco et al., 1992 Danish workers—incidence Men 72 0.7 (p 0.05) Women 5 1.2* Wigle et al., 1990 Canadian farmers 24 1.1 (0.7–1.6) Wiklund, 1983 Swedish male and female agricultural workers—incidence 268 0.8 (0.7–1.0)c ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi et al., Seveso residents—20-year follow-up 2001 Zones A, B—men 1 1.5 (0.2–12.5) women 2 1.8 (0.4–7.3) Schreinemachers, Rural or farm residents of Minnesota, Montana, 2000 and North and South Dakota Men—counties with high wheat acreage 41 0.8 (0.6–1.1) medium wheat acreage 50 0.8 (0.6–1.1) Women—counties with high wheat acreage 29 0.7 (0.5–1.2) medium wheat acreage 59 1.2 (0.9–1.8) Studies Reviewed in Update 1998 Bertazzi et al., Seveso residents—15-year follow-up 1997 Zone A—women 1 9.4 (0.1–52.3) Zone R—men 3 1.1 (0.2–3.2) women 3 0.6 (0.1–1.8) Svensson et al., Swedish fishermen (men and women) 1995 East coast Incidence 0 0.0 (0.0–0.7) Mortality 0 0.0 (0.0–1.7) West coast Incidence 20 0.8 (0.5–1.2) Mortality 6 0.7 (0.3–1.5) Studies Reviewed in VAO Bertazzi et al., Seveso residents—10-year follow-up 1989a Zones A, B, R—men 3 3.3 (0.8–13.9) women 1 0.3 (0.1–2.5)

CANCER 359 TABLE 6-20 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 756 1.3 (1.2–1.4) Navy 173 1.4 (1.2–1.6) Army 510 1.2 (1.2–1.4) Air Force 73 1.4 (1.1–1.7) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 111 1.1 (0.9–1.3) Navy 35 1.6 (1.0–2.1) Army 66 1.0 (0.7–1.2) Air Force 10 1.0 (0.5–1.8) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans—deployed vs non-deployed Incidence 204 1.1 (0.9–1.4) Mortality 14 0.6 (0.3–1.1) Pavuk et al., 2005 White Air Force comparison subjects only—incidence Serum TCDD levels (pg/g), based on model with exposure variable loge(TCDD)d Per unit increase of –loge(TCDD) in pg/g 25 2.7 (1.1–6.3) Quartiles (pg/g) 0.4–2.6 3 1.0 2.6–3.8 5 2.1 (0.4–11) 3.8–5.2 8 3.2 (0.7–15.5) 5.2 9 3.6 (0.7–17.2) Number of years served in Southeast Asia (SEA) Per year of service 25 1.1 (0.9–1.3) Quartiles (years in SEA) 0.8–1.3 3 1.0 1.3–2.1 4 1.9 (0.3–10.3) 2.1–3.7 8 3.2 (0.7–15.3) 3.7–16.4 10 4.1 (0.9–19.7) Boehmer et al., Follow-up of CDC Vietnam Experience Cohort 6 1.4 (0.4–4.9) 2004 continued

360 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-20 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2004 Akhtar et al., 2004 AFHS subjects vs national rates White AFHS Ranch Hand veterans Mortality—all * Incidence—all 17 2.3 (1.4–3.7) With tours between 1966–1970 16 2.6 (1.5–4.1) White AFHS comparison veterans Mortality—all * Incidence—all 15 1.5 (0.9–2.4) With tours between 1966–1970 12 1.5 (0.8–2.6) White AFHS subjects—incidence Who spent at most 2 years in SEA Per unit increase of –loge(TCDD) in pg/g 14 2.2 (1.3–3.9) Comparison group 3 1.0 Ranch Hand 10 TCDD pg/g in 1987 4 3.0 (0.5–16.8) 118.5 TCDD pg/g at end of service 4 7.4 (1.3–41.0) 118.5 TCDD pg/g at end of service 3 7.5 (1.1–50.2) Only Ranch Hands with 100% service in Vietnam and comparisons with 0% service in Vietnam Per unit increase of –loge(TCDD) in pg/g 14 1.7 (1.0–2.8) Comparison group 2 1.0 Ranch Hand 10 TCDD pg/g in 1987 5 3.9 (0.4–35.3) 118.5 TCDD pg/g at end of service 4 7.2 (0.9–58.8) 118.5 TCDD pg/g at end of service 3 5.5 (0.6–46.1) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence 16 1.8 (0.8–3.8) Ketchum et al., Ranch Hand (RH) veterans and comparisons 1999 through June 1997—incidence Comparisons 9 1.0 RH background-exposure 4 1.1 (0.3–4.5) RH low-exposure 6 2.6 (0.7–9.1) RH high-exposure 2 0.9 (0.2–5.6) AIHW, 1999 Australian Vietnam veterans (validation study) 380 expected —incidence 483 (342–418) CDVA, 1998a Australian Vietnam veterans (men)—incidence 2,689e 380 expected (342–418) CDVA, 1998b Australian Vietnam veterans 7e 3 expected (women)—incidence (1–8) Studies Reviewed in Update 1998 CDVA, 1997a Australian Vietnam veterans (men) 51 1.3 (0.9–1.7) CDVA, 1997b Australian National Service Vietnam veterans 16 0.5 (0.2–1.3) Clapp, 1997 Massachusetts Vietnam veterans—incidence 21 1.4 (0.7–2.9)

CANCER 361 TABLE 6-20 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Wolfe et al., 1990 Air Force Ranch Hand veterans—incidence 4 1.3 (0.3–5.2) Breslin et al., 1988 Army Vietnam veterans 145 1.0 (0.9–1.1) Marine Vietnam veterans 36 0.9 (0.6–1.5) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Cohorts are male and the endpoint is mortality unless otherwise noted. b Given when available. c 99% CI. d The original paper implied that the exposure metric for TCDD was based on actual measured serum levels of TCDD. Subsequent correspondence between the Committee and the investigators indicated that the metric was actually transformed using the natural logarithm of TCDD. e Self-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have melanoma? — Denoted by a dash in the original study. Studies in italics have been superseded by newer studies of the same cohorts. general population. The numbers of melanoma deaths observed in this study are small, and the confidence intervals are relatively wide. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re- ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of melanoma was not significantly increased (nine cases; SMR 1.21, 95% CI 0.56–2.29). Magnani et al. (1987) conducted a case–control mortality study of 99 people with melanoma and 361 controls in the United Kingdom. A JEM was used to predict exposures to various chemical agents on the basis of job title as indicated on the death certificates. Estimated risks of melanoma associated with exposure to herbicides (RR 1.2, 95% CI 0.4–4.0) and chlorophenols (RR 0.9, 95% CI 0.4–2.3) were not significantly increased. For completeness, we note here a letter to the editor by Kennedy et al. (2005). It is not evident that it was peer-reviewed, which is a standard require- ment for inclusion in the present committee’s evidentiary database of nongovern- ment reports, but no other publications on the Leiden Skin Cancer Study could be found mentioning herbicides. The letter describes results from a case–control study of squamous-cell carcinoma, basal-cell carcinoma, and melanoma without providing any details about the selection of cases and controls. Data on only male subjects were reported because relevant exposures of women were rare. Of the

362 VETERANS AND AGENT ORANGE: UPDATE 2006 47 men with melanoma, only one reported ever being exposed to herbicides. The data are insufficient to support a stable RR estimate, but the authors did document a significant risk of melanoma in men exposed to arsenic (RR 7.1), although apparently neither organic nor in the form of a herbicide, as would be of inter- est for the VAO reports. Even if it were eligible for inclusion, the paper would provide little information on the potential for an association between exposure to herbicides and melanoma. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and melanoma were published since Update 2004. Vietnam-Veteran Studies Pavuk et al. (2005) reported on cancer incidence from 1982 to 2003 in the comparison group in the Air Force Health Study (AFHS). Those Air Force veterans had served in Southeast Asia but had not been involved in spraying her- bicides during the Vietnam War, as had the Ranch Hand veterans who were the AFHS primary subjects. Of the roughly 1,800 comparison subjects enrolled in the course of the AFHS, 1,482 had serum TCDD readings used as the basis of the analyses presented here. The median TCDD concentration in the Southeast Asia comparison group (sampled in 1987) was 3.8 pg/g of lipid, and the values in the highest quartile ranged from 5.2 to 54.8 pg/g. The serum TCDD concentrations in the comparison subjects overlapped considerably with those in the Ranch Hand veterans, 43.2 percent of whom had TCDD readings in 1987 of less than 10 pg/g (see Akhtar et al., 2004). The 25 cases of melanoma were distributed as three, five, eight, and nine cases over the quartiles with increasing TCDD. Using the lowest quartile as the referent group for the other three quartiles of Southeast Asia comparison subjects, the second, third, and fourth quartiles of serum TCDD showed increasing RRs of 2.1 (95% CI 0.4–11), 3.2 (95% CI 0.7–15.5), and 3.6 (95% CI 0.7–17.2), re- spectively. The committee’s correspondence with the authors confirmed that the reported significant dose–response relationship was based on a model that used natural-logarithm transformation of the continuous variable, individual serum TCDD concentration (slope per ln [TCDD], 2.7, 95% CI 1.1–6.3; p 0.02). The results were adjusted for a number of other risk factors, including military occupation, year of birth, number of years served in Southeast Asia, body-mass index (BMI), skin reaction to sunlight exposure, and eye color. An analogous analysis on the numbers of years that each person had served in Southeast Asia did not yield a significant association with the risk of melanoma (slope per year in Southeast Asia, 1.1, 95% CI 0.9–1.3; p 0.46). Thus, an increase in the oc-

CANCER 363 currence of melanoma was found to be more specifically associated with TCDD exposure than with service in Southeast Asia. In the mortality update of the CDC VES through 2000, Boehmer et al. (2004) reported six melanoma deaths in the deployed and four in the non-deployed (CRR 1.39, 95% CI 0.39–4.93). A statistically significant increase in melanoma incidence in male Australian Vietnam veterans was found in comparison with the general Australian popula- tion (ADVA, 2005a) on the basis of 756 observed cases (SIR 1.32, 95% CI 1.23–1.41). When the analysis was stratified over the Army, Navy, and Air Force, similar significant associations with the incidence of melanoma were observed in all three branches of service. A potential confounder in the study is exposure to sunlight. The mortality experience of the above group of male Australian Vietnam vet- erans through 2001 was analyzed, again by using the rate observed in Australian men in general as the standard (ADVA, 2005b). The 111 deaths from melanoma in all the veterans showed a statistically non-significant increase (SMR 1.10, 95% CI 0.90–1.31). On the basis of 35 deaths from melanoma, mortality was significantly increased in the veterans who had served in the Navy (SMR 1.56, 95% CI 1.04–2.08), but the findings were neutral for those who had served in the Army or Air Force. A different Australian study (ADVA, 2005c) compared deployed male Army National Service veterans with non-deployed Vietnam-era veterans. That com- parison has the advantage of contrasting health outcomes in groups of men who were of similar age, health, and fitness at the time of enlistment but who differed primarily in Vietnam experience. On the basis of 204 incident cases of and 14 deaths from melanoma in the deployed veterans, neither incidence (SIR 1.13, 95% CI 0.93–1.37) nor mortality (SMR 0.56, 95% CI 0.28–1.08) was increased in comparison with the non-deployed veterans. Biologic Plausibility No animal studies have reported an increased incidence of melanoma after exposure to the compounds of interest. The biologic plausibility of the carcino- genicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis On the whole, the new occupational studies of melanoma were small and could not provide stable estimates of RR associated with herbicide exposure. The Alavanja study had a suggestive result in one subgroup (the female spouses of the private applicators), which the authors had not expected. Increased risks

364 VETERANS AND AGENT ORANGE: UPDATE 2006 in contemporary users of phenoxy herbicides would not be expected, however, if TCDD were the agent responsible for any increase in melanoma. Occupational studies reviewed previously by the VAO committees have shown a wide range of estimated RRs of melanoma, with only a few results sug- gesting an increase in the risk of melanoma in workers potentially exposed to the components of the herbicides sprayed in Vietnam. With respect to melanoma mortality, only the finding of Swaen et al. (2004) based on five skin-cancer deaths in Dutch herbicide applicators was statistically significant (SMR 3.5, 95% CI 1.2–8.3), and even this result did not explicitly exclude non-melanoma skin can- cer. The pooled international IARC cohort (Kogevinas et al., 1997) provides the most comprehensive analysis of cancer mortality in phenoxy herbicide producers and sprayers, with or without concurrent TCDD exposure, but there were only nine melanoma deaths in all the people exposed to phenoxy herbicides and no suggestion of an increased risk with or without TCDD exposure. On the basis of four exposed cases, Lynge (1993) reported a significant increase in the incidence of melanoma (SIR 4.3, 95% CI 1.2–10.9) in the cohort of Danish phenoxy her- bicide producers (whose mortality experience was included in the non-significant findings on the IARC cohort overall). The limited findings concerning mortality 20 years after environmental ex- posure arising from the Seveso accident (Bertazzi et al., 2001) show modest increases in the estimated risks in both men (SMR 1.5, 95% CI 0.2–12.5) and women (SMR 1.8, 95% CI 0.4–7.3) who resided closest to the release (in Zones A and B), but these estimates, being based on only one and two deaths from melanoma, respectively, are extremely unstable. The newly published studies of Australian servicemen who served in Viet- nam show some indication of increases in the occurrence of melanoma, but the overall interpretation is not straightforward. The incidence of melanoma is sig- nificantly increased in all male Australian Vietnam veterans in comparison with the general population (ADVA, 2005a). In the parallel study of mortality in the servicemen relative to the Australian population (ADVA, 2005b), the increase in melanoma risk is significant only in those serving in the Navy (SIR 1.6, 95% CI 1.0–2.1), who might also have had more sunlight exposure. The third Australian study (ADVA, 2005c), comparing deployed and non-deployed National Service veterans (male Army conscripts) with respect to both melanoma incidence and mortality, does not support an effect of deployment (as used as a surrogate for herbicide exposure). The mortality update on the CDC VES (Boehmer et al., 2004) does contain a somewhat, but not significantly, higher incidence of mela- noma in deployed than in non-deployed Vietnam-era veterans (SMR 1.39, 95% CI 0.39–4.93). The most persuasive evidence comes from the AFHS. The positive findings of an association between TCDD exposure and melanoma presented in Akhtar et al. (2004) are extended down into serum concentrations in the Southeast Asia comparison group in the analyses of Pavuk et al. (2005). Increases in melanoma

CANCER 365 risk in people in the second, third, and fourth quartiles of serum TCDD concen- trations were seen in comparison with the lowest quartile. The overall slope of a dose–response curve in an analytic model based on the logarithm of the continu- ous variable—each person’s serum TCDD concentration—was also statistically significant. In Akhtar et al. (2004), the findings on melanoma incidence in the Ranch Hand veterans were similarly significantly increased; they were stronger and more TCDD-specific than for any other type of cancer. Melanoma diagnoses are known to increase with screening, as was conducted in the AFHS, but this factor is less likely to bias the estimated risks when the comparison is internal, as in the AFHS reports. It is compelling that a significant dose–response relationship is found when analysis is based on individual readings for the continuous variable (serum TCDD) that is generally regarded as the most precise indicator of herbicide exposure in Vietnam. The analyses in Akhtar et al. (2004) and Pavuk et al. (2005) involve interpretations that were not part of the original study design, but, given some of the insights that have been gained in the course of the AFHS, such approaches may be justified. The results in those two publications would be more useful if they were presented in a more transparent fashion. In summary, although the collateral evidence from studies of other occupa- tional and environmental populations is inconsistent, significant associations have been demonstrated in studies of populations with well-characterized exposures to the compounds of interest (Lynge, 1993; Swaen et al., 2004); they provide evidence of an association with melanoma that may be limited by the possibility of bias or chance. The findings of the ADVA (2005a,b,c) in Australian Vietnam veterans are limited by internal inconsistency. The increase in mortality reported by the CDC VES (Boehmer et al., 2004) is consistent but far from significant. The results of the AFHS have long been anticipated as the most directly pertinent to the experience of US Vietnam veterans, so the committee was im- pressed by recent reports (Akhtar et al., 2004; Pavuk et al., 2005) of a strong dose–response relationship between serum TCDD concentrations and melanoma in this population. Some members of the committee were concerned, however, that the findings of the AFHS have not been presented in a complete and sys- tematic fashion. For example, the follow-up for the analysis of the Ranch Hand subjects (Akhtar et al., 2004) represents findings only up to 1999 (not including results of the final examination cycle), whereas the report on the Southeast Asia comparison group (Pavuk et al., 2005) includes diagnoses through 2003. The cross-sectional report (AFHS, 2005) does not provide a definitive statement of cumulative melanoma diagnoses observed in the Ranch Hand subjects through 2003 to match the data analyzed for the Southeast Asia comparison group in Pavuk et al. (2005), but the stated prevalences in the final examination cycle sug- gest that new melanoma diagnoses in the comparison subjects greatly exceeded those in Ranch Hand subjects (see Table 4-4 in Chapter 4). The committee there- fore endorses further evaluation and longitudinal analysis of the entire data set

366 VETERANS AND AGENT ORANGE: UPDATE 2006 on cancer outcomes generated in the important AFHS population. The AFHS is of questionable central relevance to the committee’s charge, but it had a persist- ing concern that there was little suggestion of an association in other relevant populations. The committee members agreed that the two published articles from the AFHS (Akhtar et al., 2004; Pavuk et al., 2005) were very strong findings based on TCDD measurements in a study population of prime interest. Several could not, however, agree to move melanoma into the limited or suggestive category, given the paucity of support from other investigated populations. Another re- straining concern was the hint in the report (AFHS, 2005) on those attending the final AFHS examination that many more new melanomas were diagnosed among the comparison veterans than in the Ranch Hand subjects, which might produce quite different results if the analyses in Akhtar et al. (2004) were rerun on the final data set. Conclusion After extensive deliberation concerning new evidence and the results of stud- ies reviewed in previous updates, the committee was unable to reach consensus as to whether the evidence concerning an association between exposure to the com- pounds of interest and melanoma met the criteria for being considered limited or suggestive or this health outcome should remain in the inadequate or insufficient classification primarily because the suggestive findings are almost exclusively from the AFHS, whose final data on both the Ranch Hand and comparison sub- jects have not yet been analyzed in a satisfactory and uniform manner. SKIN CANCER—BASAL-CELL AND SQUAMOUS-CELL CANCER (NON-MELANOMA) The preceding section on melanoma presented background information on non-melanoma skin cancer. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and skin cancer, and additional informa- tion available to the committee responsible for Update 1996 did not change that conclusion. The Update 1998 committee considered the literature on non- melanoma skin cancer separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and basal-cell or squamous-cell cancer. The Update 2000 and Update 2002 committees concurred with that conclusion. Table 6-21 summarizes the relevant studies.

CANCER 367 TABLE 6-21 Selected Epidemiologic Studies—Non-Melanoma (basal- and squamous-cell) Skin Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL New Studies Torchio et al., 1994 Italian licensed pesticide users 3 0.6 (0.1–1.8) Studies Reviewed in Update 2004 Swaen et al., 2004 Dutch licensed herbicide applicators Melanoma, squamous-cell carcinoma, and unknown skin cancer (mortality presumable attributable to melanoma) 5 3.6 (1.2–8.3) Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers (included in the IARC cohort and the NIOSH Dioxin Registry) Non-melanoma skin cancer 0 — Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides—incidence Foremen 1 16.7 (0.2–92.7) Studies Reviewed in Update 1998 Kogevinas et al., IARC cohort (men and women) 1997 Workers exposed to any phenoxy herbicide or chlorophenol 4 0.9 (0.3–2.4) Exposed to TCDD (or higher-chlorinated dioxins) 4 1.3 (0.3–3.2) Not exposed to TCDD (or higher- chlorinated dioxins) 0 —* Zhong and Rafnsson, Icelandic pesticide users (men and 1996 women—incidence) Men 5 2.8 (0.9–6.6) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states White men 425 1.1 (1.0–1.2) White women 6 1.0 (0.4–2.1) Studies Reviewed in VAO Ronco et al., 1992 Danish workers—incidence Men—self-employed 493 0.7 (p 0.05) employee 98 0.7 (p 0.05) Women—self-employed 5 0.3 (p 0.05) employee 10 0.9 (*) family worker 90 0.6 (p 0.05) Coggon et al., 1986 British MCPA production workers (included in the IARC cohort) 3 3.1 (0.6–9.0) continued

368 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-21 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ENVIRONMENTAL Studies Reviewed in Update 1998 Gallagher et al., 1996 Alberta, Canada, residents—squamous-cell carcinoma (incidence) All herbicide exposure 79 1.5 (1.0–2.3) Low herbicide exposure 33 1.9 (1.0–3.6) High herbicide exposure 46 3.9 (2.2–6.9) Alberta, Canada, residents—basal-cell carcinoma All herbicide exposure 70 1.1 (0.8–1.7) Svensson et al., 1995 Swedish fishermen East coast Incidence 22 2.3 (1.5–3.5) Mortality 0 0.0 (0.0–15.4) West coast Incidence 69 1.1 (0.9–1.4) Mortality 5 3.1 (1.0–7.1) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up (incidence) Zone A—men 1 2.4 (0.3–17.2) women 1 3.9 (0.5–28.1) Zone B—men 2 0.7 (0.2–2.9) women 2 1.3 (0.3–5.1) Zone R—men 20 1.0 (0.6–1.6) women 13 1.0 (0.6–1.9) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents—incidence Zones A, B—men 3 1.0 (0.3–3.0) women 3 1.5 (0.5–4.9) Zone R—men 20 1.0 (0.6–1.6) women 13 1.0 (0.5–1.7) Wiklund, 1983 Swedish agricultural workers—incidence 708 1.1 (1.0–1.2)c

CANCER 369 TABLE 6-21 Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Pavuk et al., 2005 White Air Force comparison subjects only (basal and squamous cell)—incidence Serum TCDD levels (pg/g), based on model with exposure variable loge(TCDD)d Per unit increase of –loge(TCDD) in pg/g 253 1.2 (0.9–1.4) Quartiles (pg/g) 0.4–2.6 50 * 2.6–3.8 59 1.2 (0.8–1.8) 3.8–5.2 71 1.5 (1.1–2.3) 5.2 73 1.4 (0.9–2.0) Number of years served in Southeast Asia (SEA) Per year of service 253 1 (0.9 –1.1) Quartiles (years in SEA) 0.8–1.3 55 * 1.3–2.1 50 0.9 (0.6–1.4) 2.1–3.7 73 1.1 (0.8–1.6) 3.7–16.4 75 1.2 (0.8–1.7) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence Basal-cell carcinoma 121 1.2 (0.9–1.6) Squamous-cell carcinoma 20 1.5 (0.8–2.8) CDVA, 1998a Australian Vietnam veterans—men (incidence) 6,936e ** CDVA, 1998b Australian Vietnam veterans—women (incidence) 37e ** Studies Reviewed in VAO Wolfe et al., 1990 Air Force Ranch Hand veterans—incidence Basal-cell carcinoma 78 1.5 (1.0–2.1) Squamous-cell carcinoma 6 1.6 (0.5–5.1) ABBREVIATIONS: AFHS, Air Force Health Study; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval. a Cohorts are male unless otherwise noted. b Given when available. c 99% CI. d The original paper implied that the exposure metric for TCDD was based on actual measured serum levels of TCDD. Subsequent correspondence between the Committee and the investigators indicated that the metric was actually transformed using the natural logarithm of TCDD. e Self-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have other skin cancers (basal-cell carcinoma, squamous-cell carcinoma)? * Information not provided by study authors. Studies in italics have been superseded by newer studies of the same cohorts.

370 VETERANS AND AGENT ORANGE: UPDATE 2006 Update of the Epidemiologic Literature Occupational Studies In reporting on cancer incidence in the AHS cohort, Alavanja et al. (2005) did not consider non-melanoma skin cancers, because they are not systematically registered in Iowa or North Carolina. Torchio et al. (1994) reported on a cohort of 23,401 Italian licensed pesticide users in the Piedmont region, which the Italian National Institute of Statistics re- ports as having high herbicide use, especially of 2,4-D and MCPA. The estimated risk of skin cancer other than melanoma was not increased (three cases; SMR 0.6, 95% CI 0.12–1.75). As in the section above on melanoma, we note here a letter to the editor by Kennedy et al. (2005) although it apparently was not peer-reviewed. They reported the frequency of exposure to herbicides of 103 men with squamous-cell carcinoma, 171 with nodular basal-cell carcinoma, and 78 with superficial mul- tifocal basal-cell carcinoma. Separate exposure rates for cases and controls were not reported in their case–control study. The ORs for herbicide exposure were 0.8 for squamous-cell carcinoma, 0.6 for nodular basal-cell carcinoma, and 0.5 for superficial multifocal basal-cell carcinoma; all have wide confidence intervals, and none is statistically significant. Environmental Studies No new environmental studies concerning exposure to the compounds of interest and non-melanoma skin cancer were published since Update 2004. Vietnam-Veteran Studies Focusing only on the Southeast Asia comparison subjects in the AFHS, Pavuk et al. (2005) reported 253 cases of basal-cell and squamous-cell carci- noma and an overall RR of 1.2 (95% CI 0.9–1.4) when the second, third, and fourth quartiles combined were compared with the first quartile for serum TCDD concentrations. A significant excess (based on 71 cases) was found for the third quartile (RR 1.5, 95% CI 1.1–2.3; p 0.03). The RR for the fourth quartile was 1.4, but it did not achieve statistical significance. The overall dose–response relationship in a model that considered individual values for serum TCDD was not statistically significant. Those results were adjusted for a number of other risk factors, including military occupation, year of birth, number of years served in Southeast Asia, BMI, skin reaction to sunlight exposure, and eye color.

CANCER 371 Biologic Plausibility Studies in mice that have been designed to determine carcinogenic actions of TCDD generally support the idea that TCDD promotes the formation of skin papillomas and squamous-cell carcinomas (Dunson et al., 2000; Poland et al., 1982; Wyde et al., 2004). However, the observation of the tumor-promoting ef- fects of TCDD only in specific strains (the genetically initiated TgAc [Dunson et al., 2000; Wyde et al., 2004] and the hairless strain [Hebert et al., 1990; Poland et al., 1982] but not such strains as the ICR strain [Wu et al., 2004]) indicates that activation of multiple carcinogenic pathways is required. Similar studies performed in the Syrian golden hamster revealed that treatment with TCDD alone was sufficient for the development of squamous-cell carcinomas of the facial skin (Rao et al., 1988). Cacodylic acid is a well-known skin carcinogen in humans, but studies in animal models have failed to demonstrate its carcinogenic action in the skin (Cohen et al., 2006). The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis The new results in the Pavuk et al. study, although intriguing, demonstrate only a small RR that is not statistically significant, and the dose–response rela- tionship also is not statistically significant. The only statistically significant result was found in the third, rather than the fourth, quartile of exposure to TCDD, although similar estimated risks were found in the second and fourth quartiles. On the basis of the new studies and in accord with the results of reports previ- ously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and basal-cell or squamous-cell cancer. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and basal-cell or squamous-cell cancer. BREAST CANCER Breast cancer (ICD-9 174 for women, ICD-9 175 for men) is the second- most common type of cancer (after non-melanoma skin cancer) in women in the United States. ACS estimated that 212,920 women would receive diagnoses of breast cancer in the United States in 2006 and that 40,970 would die from it

372 VETERANS AND AGENT ORANGE: UPDATE 2006 (Jemal et al., 2006). Overall, those numbers represent about 31 percent of the new cancers and 15 percent of cancer deaths in women. Incidence data on breast cancer are presented in Table 6-22. Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence is higher in whites than in blacks. Estab- lished risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early men- arche, late onset of menopause, and either no pregnancies or first full-term preg- nancy after the age of 30 years. A pooled analysis of six large-scale prospective studies of invasive breast cancer showed that alcohol consumption over the range of consumption reported by most women was associated with a linear increase in incidence in women (Smith-Warner et al., 1998). The potential of other personal behavioral and environmental factors (including exogenous hormones) to affect breast-cancer incidence is being studied extensively. Most of the roughly 10,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have recently reached menopause. Given the high incidence of breast cancer among older and post- menopausal women in general, on the basis of demographics alone it is expected that the breast-cancer burden in female Vietnam veterans will increase in the near future. Breast cancer occurs primarily in women, and the vast majority of breast- cancer epidemiologic studies involve women, but it also occurs in men (ACS, 2006). Reported instances of male breast cancer are noted, but the committee’s conclusions are based on the studies in women. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and breast cancer. Additional information TABLE 6-22 Average Annual Incidence (per 100,000) of Breast Cancer in Women in the United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Men 1.34 1.35 2.17 2.7 2.4 6.4 3.8 4.0 5.5 Women 249.0 258.1 227.6 327.2 340.6 281.3 388.4 408.3 333.1 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

CANCER 373 available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 6-23 summarizes the relevant research. Update of the Epidemiologic Literature Occupational Studies Three reports on breast-cancer risk in spouses in the AHS have been pub- lished since Update 2004. Alavanja et al. (2005) identified 474 cases of breast cancer diagnosed through 2002 in the 32,347 spouses of pesticide applicators. No excess breast cancer was observed compared with the general population of North Carolina and Iowa (SIR 0.99, 95% CI 0.90–1.08). It is unclear whether an association between the compounds of interest and breast-cancer risk, if one existed, would be strong enough to increase the estimated risk in such a broadly categorized exposure group. Engel et al. (2005) later conducted more detailed analyses on breast cancer in the same women in relation to type of chemical ex- posure. The association was null for exposure to phenoxy herbicides as a broad category, considering either direct chemical use by the women (RR 0.8, 95% CI 0.6–1.1) or use by the husbands of women who did not apply the chemicals themselves (RR 1.1, 95% CI 0.7–1.8). The results did not vary with duration of exposure, menopausal status, or state of residence (North Carolina vs Iowa). When exposure to 18 specific herbicides was considered, a significant increase in risk was seen only in women whose husbands used trichlorophenoxy propionic acid (2,4,5-TP) (RR 2.0, 95% CI 1.2–3.2). Results for 2,4-D and 2,4,5-T were null. Blair et al. (2005a) analyzed cancer mortality for 1994–2000 in the same cohort and reported no increase in risk of death from breast cancer in the AHS spouses (SMR 0.9, 95% CI 0.7–1.1); the few women among the private ap- plicators had a similar risk with wider confidence limits. Again, in this analysis the use of broad exposure categories could mask an association with the specific herbicides of interest. In New Zealand, ’t Mannetje et al. (2005) followed the mortality experience of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers from 1969 and 1973, respectively, through 2000. One woman and one man died from breast cancer in the producer group and none of the sprayers. Estimation of breast- cancer risk in this cohort is extremely imprecise because of the small numbers. Mills and Yang (2005) conducted a case–control study in Hispanic agricul- tural workers in California. They estimated breast-cancer risk in relation to union work histories and pesticide use as recorded in state databases. They considered 13 specific chemicals, including 2,4-D. With non-exposed women as the referent group, no association with 2,4-D use was seen in women who had breast cancer diagnosed in 1988–1994. For cases diagnosed in the later period of observation (1995–2001), however, high exposure to 2,4-D was associated with a significant

374 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-23 Selected Epidemiologic Studies—Breast Cancer Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a OCCUPATIONAL New Studies McLean et al., IARC cohort of pulp and paper workers 2006 Exposure to nonvolatile organochlorine compounds Never 21 0.9 (0.6–1.4) Ever 32 0.9 (0.6–1.3) Alavanja et al., US Agriculture Health Study—incidence 2005 Private applicators (men and women) 27 1.1 (0.7–1.6) Spouses of private applicators ( 99% women) 474 1.0 (0.9–1.1) Commercial applicators (men and women) 1 0.6 (0.1–3.5) Blair et al., 2005a US Agriculture Health Study—mortality Private applicators (men and women) 3 0.9 (0.2–2.7) Spouses of private applicators ( 99% women) 54 0.9 (0.7–1.1) Engel et al., 2005 US Agriculture Health Study, wives of private applicators—incidence Wives own use of phenoxy herbicides 41 0.8 (0.6–1.1) 2,4-D 41 0.8 (0.6–1.1) Husbands’ use of phenoxy herbicides 110 1.1 (0.7–1.8) 2,4-D 107 0.9 (0.6–1.4) 2,4,5-T 44 1.3 (0.9–1.9) 2,4,5-TP 19 2.0 (1.2–3.2) Mills and Yang, Hispanic agricultural farm workers (women) 2005 Cancer diagnosis 1987–1994 Low 2,4-D use 12 0.6 (0.2–1.9) High 2,4-D use 8 0.6 (0.2–1.7) Cancer diagnosis 1995–2001 Low 2,4-D use 19 2.2 (1.0–4.9) High 2,4-D use 21 2.1 (1.1–4.3) ’t Mannetje et al., Phenoxy herbicide producers (men and women) 2005 Women 1 1.3 (0.0–7.2) Men 1 32 (0.8–175) Phenoxy herbicide sprayers ( 99% men) 0 0.0 (*) Studies Reviewed in Update 2000 Duell et al., 2000 Female farm workers and residents in North Carolina Used pesticides in the garden 228 2.3 (1.7–3.1) Laundered clothes for pesticide user 119 4.1 (2.8–5.9) Studies Reviewed in Update 1998 Kogevinas et al., IARC cohort 1997 Women (identical with Manz et al., 1991) 9 2.2 (1.0–4.1) Men 2 2.6 (0.3–9.3)

CANCER 375 TABLE 6-23 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states Men—white 18 0.7 (0.4–1.2) nonwhite 4 1.7 (0.5–4.4) Women—white 71 1.0 (0.8–1.3) nonwhite 30 0.7 (0.5–1.0) Kogevinas et al., IARC cohort—women 7 0.9 (0.4–1.9) 1993 Studies Reviewed in VAO Ronco et al., 1992 Danish and Italian farm workers Male farmers 5 0.5* Female farmers 41 0.9* Female family workers 429 0.8 (p 0.05) Manz et al., 1991 German production workers—men and women (included in the IARC cohort) Women 9 2.2 (1.0–4.1) Saracci et al., 1991 IARC cohort—exposed subcohort (men and women) Men 2 3.5 (0.4–12.5) Women 1 0.3 (0.0–1.7) Lynge, 1985 Danish male and female production workers— incidence (included in the IARC cohort) Women 13 0.9* Wiklund, 1983 Swedish male and female agricultural workers—incidence 444 0.8 (0.7–0.9)b ENVIRONMENTAL New Studies Reynolds et al., Women undergoing breast biopsies in San 2005 Francisco area hospitals—79 breast–cancer cases vs 52 controls with benign breast conditions—incidence Total TEQs (pg/g) in adipose breast tissue 14.0 24 1.0 14.1–20.9 22 0.7 (0.3–1.9) 21.0 33 0.3 (0.3–2.0) p-trend 0.99 Reynolds et al., California Teachers Study cohort 2004 Residential proximity to use of “endocrine disruptors” (including 2,4–D and cacodylic acid) Quartiles of use (lb/mi2) 1 1,027 1.0 1–21 274 1.0 (0.8–1.1) 22–323 114 0.9 (0.7–1.1) 324 137 1.0 (0.9–1.3) continued

376 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-23 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in Update 2002 Warner et al., 2002 Seveso Women’s Health Study—981 women who were infants to age 40 when exposed—incidence With 10-fold increase in TCDD level 15 2.1 (1.0–4.6) Revich et al., 2001 Residents of Chapaevsk, Russia—women 58 2.1 (1.6–2.7) Holford et al., 2000 Patients at Yale-New Haven hospital with breast-related surgery; dioxin-like congener 156 * 0.9 (0.8–1.0) Studies Reviewed in Update 2000 Bertazzi et al., Seveso residents—20-year follow-up 2001 Zone A, B—women 14 0.7 (0.4–1.3) Bagga et al., 2000 Women receiving medical care in Woodland Hills, California 73 NS Demers et al., 2000 Women in Quebec City—newly diagnosed 314 NS Høyer et al., 2000 Female participants of Copenhagen City Heart 195 Overall survival Study RR 2.8 (1.4–5.6) Studies Reviewed in Update 1998 Bertazzi et al., Seveso residents—15-year follow-up 1997 Zone A—women 1 0.6 (0.0–3.1) Zone B—women 9 0.8 (0.4–1.5) Zone R—women 67 0.8 (0.6–1.0) Studies Reviewed in Update 1996 Bertazzi et al., Seveso residents—10-year 1993 follow-up—incidence Zone A—women 1 0.5 (0.1–3.3) Zone B—women 10 0.7 (0.4–1.4) Zone R—women 106 1.1 (0.9–1.3) men 1 1.2 (0.1–10.2) Studies Reviewed in VAO Bertazzi et al., Seveso residents—10-year follow-up 1989b Zone A—women 1 1.1 (0.1–7.5) Zone B—women 5 0.9 (0.4–2.1) Zone R—women 28 0.6 (0.4–0.9) VIETNAM VETERANS New Studies ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 7 0.9 (0.4–1.9) Navy 1 0.6 (0.0–3.3) Army 5 1.0 (0.3–2.2) Air Force 1 1.1 (0.0–6.3)

CANCER 377 TABLE 6-23 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 4 2.2 (0.6–5.4) Navy 1 2.5 (0.0–13.5) Army 3 2.5 (0.5–7.2) Air Force 0 0.0 (0.0–14.6) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans—deployed vs non-deployed 0 — Incidence 0 0.0 (0.0–2.4) Mortality * Boehmer et al., Follow-up of CDC Vietnam Experience Cohort 0 — 2004 Studies Reviewed in Update 2002 Kang et al., 2000 Female Vietnam veterans 170 1.2 (0.9–1.5) Studies Reviewed in Update 2000 CDVA, 1998b Australian Vietnam veterans—women 17c 5 expected (2–11) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans—men 3 5.5 (1.0– 10.0) Studies Reviewed in Update 1996 Dalager et al., 1995 Female US Vietnam veterans 26 1.0 (0.6–1.8) Studies Reviewed in VAO Thomas et al., Female US Vietnam veterans 17 1.2 (0.6–2.5) 1991 ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, Inter- national Agency for Research on Cancer; NS, not significant; PCB, polychlorinated biphenyls; RR, relative risk; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalency. a Given when available. b 99% CI. c Self-reported medical history. Answer to question: “Since your first day of service in Vietnam, have you been told by a doctor that you have breast cancer?” * Information not provided by study authors. Studies in italics have been superseded by newer studies of the same cohorts. increase in breast cancer (OR 2.14, 95% CI 1.06–4.32), and low exposure was associated with a similar increase (OR 2.16, 95% CI 0.95–4.93). It is not clear why a positive association was apparent only in the later years of observation, but it is conceivable that risk increased as latency and exposure duration increased. Individual-level data on established breast-cancer risk factors were not available; county-level data on fertility and socioeconomic status were used as surrogates in adjusted analyses. That is an important limitation in a breast-cancer study because misclassification of established risk factors as covariates can introduce substantial

378 VETERANS AND AGENT ORANGE: UPDATE 2006 bias. However, fertility rates by county were inversely associated with breast- cancer risk in subjects in this study, so this ecologic variable might have been capturing some of the confounding that could occur because of different repro- ductive patterns between cases and controls. The strengths of this study—which bears on 2,4-D exposure only, not dioxins—include the use of a comprehensive statewide cancer registry for ascertainment of breast-cancer status and unbiased exposure estimation because of linkage of individual work records to a detailed database on agricultural chemical use. Environmental Studies Reynolds et al. (2004) used a geographic information system (GIS) to link data on pesticide use to residential histories of women in the California Teach- ers Study cohort. Two compounds of interest, 2,4-D and cacodylic acid, were included among 34 chemicals in a category labeled endocrine disruptors but were not addressed in any specific analyses. Residential proximity to use of chemicals in the entire category was not associated with breast-cancer risk (for the heaviest vs the lowest exposure intensity, RR was 1.03, 95% CI 0.86–1.25). It is not clear how many subjects in the analysis had substantial exposure to the compounds. In another GIS analysis, Brody et al. (2004) compared residential proximity to pesticide sources in people with breast cancer and controls in Massachusetts. No associations were observed; however, the relevance of the study is limited by uncertainty in the extent of exposure to any of the compounds of interest. Mills and Yang (2006) computed RRs of breast cancer among Latina women in California according to countywide data on pesticide use. Significant increases in risk were reported in association with two organochlorines (methoxychlor and toxaphene); however, risk estimates were not provided for any of the specific compounds of interest. The analysis carries less weight than the previously de- scribed study on Latina farm workers by the same authors because, although the number of breast cancers is much greater, the proportion of women significantly exposed to the chemicals is much lower. Three recent studies are noteworthy for having measured organochlorines in adipose tissue in breast-cancer cases and controls, although two of them are not very informative, because of lack of focus on the specific compounds of interest. The first, a methodologic study by Petreas et al. (2004), is discussed in Chapter 5 in connection with exposure considerations. Raaschou-Nielsen et al. (2005) compared 409 postmenopausal Danish women with breast cancer to an equal number of matched controls selected from a large research cohort. Fourteen pesticides and 18 polychlorinated biphenyl (PCB) congeners were measured in adipose tissue from the buttocks; women with higher adipose-tissue concentrations of the compounds did not have a higher risk of breast cancer. In fact, the study found strong inverse associations with risk of estrogen-receptor-negative breast cancer in women with the highest concentra-

CANCER 379 tions of total PCBs and several organochlorine pesticides (p 0.007 for trend across quartiles of total PCBs). The investigators speculate that the inverse as- sociations could have resulted from higher fish consumption by controls or from more rapid metabolic conversion of precursors to proximal carcinogens by the women with cancer. The study is noteworthy because of its size and because it is the first to use adipose-tissue organochlorines in a prospective analysis of breast- cancer risk. However, its relevance for the purposes of the present committee is limited by the lack of TCDD measurement and by the extreme weakness of the dioxin-like activity of the PCB congeners. Reynolds et al. (2005) measured dioxin in breast adipose tissue obtained from 79 women with breast cancer and 52 controls with benign breast conditions. They found no associations between any of 17 polychlorinated dibenzodioxins and dibenzofurans with substitutions in the 2, 3, 7, or 8 positions. When all mea- sured compounds were combined as international toxic equivalent units, the OR for the highest tertile vs the lowest was 0.73 (95% CI 0.27–1.95). Although small and lacking in statistical power, the study is unique in its focus on the target-organ exposure and the specific compounds of interest. Vietnam-Veteran Studies In the mortality update of the CDC VES of only male subjects through 2000, Boehmer et al. (2004) reported a single case of breast cancer in the non-deployed. Similarly, the updates on the health status of Australian Vietnam veterans reported only on male veterans but included scattered breast-cancer cases. No increase was seen when veterans were compared with the general population of Australia in incidence (SIR 0.90, 95% CI 0.36–1.86) (ADVA, 2005a), but four deaths produced a non-significant increase in mortality (SMR 2.15, 95% CI 0.58–5.42) (ADVA, 2005b). In the comparison of deployed with non-deployed Vietnam vet- erans (ADVA, 2005c), only two breast-cancer cases were identified, both in the non-deployed, and no deaths from this type of cancer. Biologic Plausibility All the experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are weakly genotoxic if at all. However, TCDD is a demonstrated carcinogen in animals and is classified as a human carcinogen because of its ability to act as a strong tumor promoter. The possible general mechanisms by which TCDD may exert those effects are discussed in Chapter 3. With respect to breast cancer, studies performed in laboratory animals (Sprague-Dawley rats) indicate that the effect of TCDD may depend on the age of the animal. For example, TCDD exposure was found to inhibit mammary-tumor growth in the adult rat (Holcombe and Safe, 1994) but to increase tumor growth in the neonatal rat (21 days old) (Desaulniers et al., 2001). Other studies have

380 VETERANS AND AGENT ORANGE: UPDATE 2006 failed to demonstrate a TCDD effect on mammary-tumor incidence or growth (Desaulniers et al., 2004). Those observations may indicate a close association between the development of mammary cancers and mammary gland differentiation. Agents capable of disrupting the ability of the normal mammary epithelial cell to enter or maintain its appropri- ate status (a proliferative, differentiated, apoptotic state), to maintain its appropriate architecture, or to alter key hormone (estrogen) signaling are likely to act as carci- nogenic agents (Fenton, 2006; McGee et al., 2006). In that light, it is interesting that postnatal exposure of pregnant rats to TCDD has been found to alter proliferation and differentiation of the mammary gland (Birnbaum and Fenton, 2003; Vorderstrasse et al., 2004). Thus, the effect of TCDD may depend on the timing of the exposure and may affect mammary-tumor development only if the exposure occurs during a specific window during mammary development. The breast is the only human organ that does not fully differentiate until it becomes ready for use; nulliparous women have less-differentiated breast lobules, which are presumably more vulnerable to carcinogenesis. The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis Recent results from the AHS cohort generally do not support the hypoth- esis that exposure to the compounds in Agent Orange increases breast-cancer incidence or mortality in women, although exposure to the specific compounds of interest was not specified. Increased risks observed in one subgroup whose husbands worked with 2,4,5-TP will require further study and confirmation; this finding could have arisen by chance. Recent studies of environmental exposure found null associations; however, exposures were of questionable relevance. Two studies of organochlorine concentrations in adipose tissue failed to find any evi- dence of increased risk in association with higher adipose concentrations; in fact, the more relevant study found the risk in the highest tercile of dioxin concentra- tions in breast fat was lower than in the lowest tercile of dioxin concentrations, although not significantly so. One study published since the last update does provide some evidence of an association between exposure to 2,4-D and breast-cancer risk in female farm- workers in California (Mills and Yang, 2005). The study is limited by lack of detailed information on potential confounding factors and lack of evidence of a dose–response relationship, but it is large and the investigators were able to estimate individual exposures by linking work histories to an extensive database on pesticide use. The committee considered the new information in the context of the cumula- tive data from studies reviewed in previous updates. Results of several prior stud- ies lend support to the hypothesis that there is an association between exposure to

CANCER 381 the compounds of interest, specifically, studies by Kogevinas et al. (1997), Kang et al. (2000), Revich et al. (2001), and Warner et al. (2002). The first of those studies is a mortality study of a large multinational cohort of workers exposed to phenoxy herbicides or chlorophenols in manufacturing or spraying (Kogevinas et al., 1997). In women specifically exposed to TCDD and higher chlorinated dioxins, there were nine deaths from breast cancer vs 4.17 expected (SMR 2.16, 95% CI 0.99–4.10), whereas there was no appreciable risk in other women in the cohort. All nine deaths occurred in the German her- bicide plant that accounted for most of the exposure of women to TCDD. The breast-cancer SMR for this plant alone was 2.84 (95% CI 1.30–5.39). There were also two deaths from breast cancer in the multinational cohort in men exposed to TCDD and higher chlorinated dioxins; this is more than expected for this rare tumor, but such a result could have arisen by chance. Kang et al. (2000) reported an increased OR for breast cancer in a cross- sectional study comparing female Vietnam veterans with non-Vietnam veterans (multivariate OR 1.18, 95% CI 0.91–1.51). Revich et al. (2001) calculated SMRs for women occupationally or environ- mentally exposed to dioxins in Chapaevsk, Russia, the site of a large chemical plant. Substantially increased concentrations of dioxins were measured in soil, drinking water, and breast milk in Chapaevsk and in the serum of people who worked in the factory or lived nearby. The SMR for breast cancer in the town of Chapaevsk, with 58 observed deaths and expected numbers based on rates for the entire region, was significantly increased (SMR 2.1, 95% CI 1.6–2.7). That result has limited weight because women in the town were exposed to numerous toxic chemicals, and, although widespread contamination with dioxin was docu- mented, it is difficult to attribute the breast-cancer excess to dioxins alone. Finally, in a study of women exposed in Seveso (Warner et al., 2002), there was a significant association between lipid-adjusted serum TCDD concentrations and breast-cancer incidence (RR 2.1 for a 10-fold increase in serum TCDD, 95% CI 1.0–4.6). The study found no difference in the risk estimate after com- prehensive adjustment for established or potential breast-cancer risk factors. It is important to note that the Seveso Women’s Cohort Study ascertained breast- cancer status 20–22 years after the Seveso explosion by interview followed by medical-record verification; the study did not include three women who had already died from breast cancer before the interviews took place. The committee believes that the recent data from the study by Mills and Yang (2005), although not persuasive in themselves, lend additional weight to an association between the relevant herbicide exposures and breast-cancer risk. This study has reasonable size and relatively specific exposure information but is limited chiefly by the data available to control for confounding. Among the four earlier studies contributing to the committee’s view, two have highly specific exposure data (related to occupational exposure to phenoxy herbicides and to Seveso), one reports an increased risk in women living in an area with

382 VETERANS AND AGENT ORANGE: UPDATE 2006 documented heavy dioxin contamination (Chapaevsk), and one reports an in- creased risk in female Vietnam veterans that does not achieve the conventional level of statistical significance. Each study has limitations or weaknesses that keep its conclusions about the association in question from being definitive. Some members of the committee considered the body of evidence as a whole to be suggestive of an association; for others, the few modestly positive results associated with a diversity of exposures suggested chance findings rather than a coherent picture. Further laboratory and epidemiologic work on this association should be pursued. The main reason for the unresolved division in the committee’s opinion concerning the adequacy of the available evidence to support an association be- tween breast cancer and exposure to the components of the herbicides sprayed in Vietnam was differing individual views about the specificity and relevance of the studied exposures for the population of primary concern to the committee, Viet- nam veterans. Overall, the committee was impressed by the positive results from Seveso, but several members considered this a very small sample upon which to anchor an association. The degree to which the profile of chemicals contributing to total toxicity equivalency (TEQ) in the more positive epidemiologic studies dif- fered from that of Vietnam veterans diminished the conviction of some members that these results constituted fully relevant evidence. Conclusion After extensive deliberation concerning the new evidence and the results of studies reviewed in previous updates, the committee was unable to reach consensus as to whether the evidence of an association between exposure to the compounds of interest and breast cancer met the criteria for being considered limited or suggestive or whether concerns about chance, bias, and confounding remained so substantial that breast cancer should remain in the inadequate or insufficient classification. CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM This section addresses cancers of the cervix (ICD-9 180), endometrium (also referred to as the corpus uteri; ICD-9 182.0–182.1, 182.8), and ovary (ICD-9 183.0). Other cancers of the female reproductive system that are infrequently reported separately are unspecified cancers of the uterus (ICD-9 179), placenta (ICD-9 181), fallopian tube and other uterine adnexa (ICD-9 183.2–183.9), and other female genital organs (ICD-9 184); any findings on these cancers would be included in this section. It also presents statistics on other cancers of the female reproductive system. ACS estimates of the numbers of new female reproductive- system cancers in the United States in 2006 are presented in Table 6-24, with

CANCER 383 genital-system cancers representing roughly 11 percent of new cancer cases and 10 percent of cancer deaths in women (Jemal et al., 2006). The incidences of and risk factors for those diseases vary (Table 6-25). Cer- vical cancer occurs more often in blacks than in whites, whereas whites are more likely to develop endometrial and ovarian cancer. The incidence of endometrial and ovarian cancer is increased among older women and among those with posi- tive family histories. Use of unopposed estrogen hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of endometrial cancer. HPV infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer. Use of oral contraceptives is associated with a substantial reduction in the risk of ovarian cancer. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between ex- posure to the compounds of interest and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update TABLE 6-24 Estimates of New Cases and Deaths in 2004 in United States for Selected Cancers of the Female Reproductive Systema Site New Cases Deaths Cervix 9,710 3,700 Endometrium 41,200 7,350 Ovary 20,180 15,310 Other female genital 2,420 2,420 a ACS (2006). TABLE 6-25 Average Annual Incidence (per 100,000) of Female Genital System Cancers in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black All genital sites 85.5 89.5 61.7 119.3 126.3 80.0 151.1 156.5 145.3 Cervix 11.7 10.9 15.3 11.8 10.8 17.8 13.2 11.4 25.8 Endometrium 45.5 48.8 24.6 68.6 73.7 36.6 88.6 93.0 77.1 Ovary 22.8 24.2 15.1 31.5 33.9 17.8 39.3 42.0 30.7 Other genital organs 1.1 1.1 0.6 1.5 1.7 0.9 2.7 2.6 1.2 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003.

384 VETERANS AND AGENT ORANGE: UPDATE 2006 1998, Update 2000, Update 2002, and Update 2004 did not change that conclu- sion. Tables 6-26, 6-27, and 6-28 summarize the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies In the analysis of cancer incidence in the AHS, Alavanja et al. (2005) re- ported an excess of ovarian cancer in pesticide applicators (SIR 2.97, 95% CI 1.28–5.85) but a significantly reduced incidence in spouses of farmer applicators (SIR 0.55, 95% CI 0.38–0.78). Blair et al. (2005a) observed parallel results for mortality in the same cohort: death from ovarian cancer was increased in applicators (on the basis of only four deaths) but not in farmer spouses. Neither incidence of nor mortality from other female reproductive cancers (combined) was reported to be increased in the analyses. No new environmental or Vietnam-veteran studies concerning exposure to the compounds of interest and female reproductive cancer were published since Update 2004. Biologic Plausibility No animal studies have reported an increased incidence of female reproduc- tive cancer after exposure to the compounds of interest. One study (Kociba et al., 1978), however, showed a reduced incidence of uterine tumors in rats fed TCDD at 0.1 mg/kg of diet for 2 years. The biologic plausibility of the carcinogenicity of the compounds of interest in general is summarized at the end of this chapter. Synthesis Two analyses of the same cohort found increased incidence of and mortality from ovarian cancer in women who had been engaged in pesticide application. The weight of those studies for the present purposes is limited by the lack of de- tail on chemical exposures and the absence of data that would allow for control of confounding. Future studies of ovarian cancer should be watched carefully, particularly studies that use biomarkers of exposure or more detailed chemical- exposure histories.

CANCER 385 TABLE 6-26 Selected Epidemiologic Studies—Cervical Cancers Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a OCCUPATIONAL Studies Reviewed in Update 1998 Kogevinas et al., IARC cohort (men and women) 1997 Workers exposed to any phenoxy herbicide or chlorophenol 3 1.1 (0.2–3.3) Exposed to TCDD (or higher-chlorinated dioxins 0 0.0 (0.0–3.8) Not exposed to TCDD (or higher- chlorinated dioxins) 3 1.8 (0.4–5.2) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states Whites 6 0.9 (0.3–2.0)