National Academies Press: OpenBook

Indoor Pollutants (1981)

Chapter: VII. Health Effects of Indoor Pollution

« Previous: VI. Monitoring and Modeling of Indoor Air Pollution
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 302
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 303
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 304
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 305
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 306
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 307
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 308
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 309
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 310
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 311
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 312
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 313
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 314
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 315
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 316
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 317
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 318
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 319
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 320
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 321
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 322
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 323
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 324
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 325
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 326
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 327
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 328
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 329
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 330
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 331
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 332
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 333
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 334
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 335
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 336
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 337
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 338
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 339
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 340
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 341
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 342
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 343
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 344
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 345
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 346
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 347
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 348
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 349
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 350
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 351
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 352
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 353
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 354
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 355
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 356
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 357
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 358
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 359
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 360
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 361
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 362
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 363
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 364
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 365
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 366
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 367
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 368
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 369
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 370
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 371
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 372
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 373
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 374
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 375
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 376
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 377
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 378
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 379
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 380
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 381
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 382
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 383
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 384
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 385
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 386
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 387
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 388
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 389
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 390
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 391
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 392
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 393
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 394
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 395
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 396
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 397
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 398
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 399
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 400
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 401
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 402
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 403
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 404
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 405
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 406
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 407
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 408
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 409
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 410
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 411
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 412
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 413
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 414
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 415
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 416
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 417
Suggested Citation:"VII. Health Effects of Indoor Pollution." National Research Council. 1981. Indoor Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/1711.
×
Page 418

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.

vIT HEALTH EE.Fk~TS OF INDOOR POLLUTION I NTRODUCTION The Committee, charged with characterizing the quality of the indoor environment and determining the potential adverse health effects o f pollutants in that environment, selected the following pollutants for detailed discussion: radon and radon progeny, formaldehyde and other organic substances, fibrous building materials, combustion products {resulting from combustion of fuels in space-heating, water-heating, cooking, hobbies and crafts, etc. I, involuntary smoking, airborne agents of contagion, and airborne allergen. . These are obviously only examples of hazardous pollutants. They were chosen because there was a large volume of Published material available on the sources of their presence Indoors that could be used to document the adverse ef feats of human exposure to them. The sources of these and other pollutants are described in Chapter TV; the biologic responses to the selected pollutants are discussed here. ~ t is beyond the scope of this report to list all the pollutants found indoors that are hazardous to human health. - ~ Some pollutant sources have been known for a long time but only recently recognized as important. Cigarette-~moking is an example; although the smoke components that cause adverse health effects need more study, considerable progress has been made, as repor~ced in This chapter. The examples given in this chapter make it plain that humans are exposed to a variety of potentially hazardous indoor pollutants from diverse sources. It is hoped that this report will encourage researchers to broaden the list of hazardous indoor pollutants and to characterize the hazards, so that the general public and those responsible for pollution control and abatement can be informed. Throughout this report, pollutants are mentioned without discussion of their health effect.. part of the Committee, but rather reflects a decision that the discussion here be adequate to show that there are indoor pollutants that cause adverse health effects in humans. The reader's attention is directed to Chapter lIT, which offers some recommendations for further health research with respect to there pollutants, for further exposure This does not constitute an oversight on tne 302

303 studies, and for public education about effective ways of reducing exposure to many contaminants encountered indoors. Pollutants are inhaled, ingested, and absorbed. They may have effects at their first point of contact with the body, or they may affect internal organs. They nay be changed physically or chemically (metabolically) in the process of exerting their effects, or they may undergo intermediate physical or metabolic changes before exerting an effect. They may be stored in tissue for a time and be released later; many of them are eventually excreted. Their own behavior helps to shape the mechanisms of their effects. Pollutants may act independently, antagonistically, or synerg istically. Inhalation is generally the most important route by which toxic substances enter the body. Inhaled substances may exert their effects in the lungs, or they may pass from the lungs to other organ systems in blood, lymph, etc. Ingestion is far less common than inhalation as a route of exposure, but is important for some toxic substances, such as lead, arsenic, and mercury. In addition to the direct physical or chemical effect of ingested substances in the gastrointestinal tract, they may pass through the tract into the blocPd and be distributed to other organs. Liquid and vapor-phase pollutants may be absorbed through the skin and affect the skin, pass through the skin and then conjugate with tissue protein, or enter the bloodstream and be distributed further. 2} 24 2S Environmental agents may exert their effects either by physical or by chemical-phy~iologic (enzymatic) mean.. The full toxic potential of most substances is usually not expressed in normal healthy people, because of the body's defense mechanisms and mechanisms of elimination or because the substances are sequestered in inactive forms at various tissue sites (bone, skin, hair, and nails). However, impairment of the body~s defensive processes may lead to increased toxicity, owing to the higher concentrations of the substances that build up when the usual means of elimination or reduction are blocked. Effects can occur metabolically at the cell or organ level. Various trace substances (e.g., halogenated hydrocarbons and trace metals) can have their effects at both levels. 13 21 24 25 Some physical signs give evidence of primary toxicity, such as contact with substances that produce irritation, inflammation, or contraction. Some gases, such as carbon monoxide and nitrogen dioxide, when inhaled can affect the body's capacity to absorb oxygen. Secondary mechanisms of toxicity include metabolic alteration of the substance and accumulation of the byproducts from the initial action of the pollutant. Some substances are detoxified by metabolic processes (oxidation, reduction, and synthesis}, and the detoxification mechanisms may themselves cause damage, as in the oxidation of alcohol to formaldehyde and the reduction of arsenic or manganese, which may produce more toxic forms. Respiratory effects can be directly attributed to only a few pollutants encountered at high concentrations indoors: nitrogen dioxide, carbon monoxide, formaldehyde, and probably particles are important in this regard.

304 Physical factors (such as temperature, humidity, noise, nonionizing radiation, and light} and their effects are discussed in Chapters Iv and VITI; knowledge of their effects in the indoor environment is sketchy and difficult to assess. Information on the health effects of pollution due to consumer products in general has the same limitations and is treated in the same way. A variety of trace metals may be present indoors as a result of filtration of outdoor sir and as ~ result of indoor sources of pollutants. These trace metals are also found in the domestic water and in the diet. Some of them, especially lead and mercury, have adverse health effects.5 ~ 15 Exposure to mercury indoors may result from spills of liquid mercury and deterioration of paint. Mercury vapor is quickly and efficiently absorbed by the lung and may be absorbed through the skin.22 Although much of the body burden of lead may come from the diet, the combined effects of air, soil, house dust, and water as sources o' indoor lead are appreciable. ~ i' 26 The effects of lead and mercury on the brain are well known ~ ~ ~ ~ ° ~ ~ - 2 ~ ~ 2 2 ~ 2 ~ - 2 ~ Behavioral dysfunctions caused by lead may occur through modification of the enzymatic response to a wide variety of toxic agents and through interference with neuromuscular and ganglionic transmission.' i . Gastrointestinal symptoms may be produced by inhalation of toxic substances, such a. lead and mercury, that reach the gastrointestinal tract through the bile duct.. 22 Organic mercury is also hepatotoxic and may cause kidney damage by destroying cells in the tubular system. 27 Lead and arsenic deposited in the kidney at low concentrations may produce sensitization to damage by endotoxins or exotoxins, such as analgesics and bacteria, although this is still debatable. Mercuric chloride may produce acute renal failure.22 Mercury has toxic effects on the thyroid and therefore may have further systemic effects. I' Cadmium interacts with other nutrients and may be stored in the kidney and damage capillaries there. 7 t' 27 28 It also accumulates in the liver at concentrations that depend on age and smoking habits., Lead can inhibit heme synthesis,~3 especially in school-age children. Lead, zinc, and delta-aminolevulinic acid (ALA-D} interact, and porphyrins (free erythrocyte porphyrins and zinc protoporphyrins) are active in the blood; that activity determines the influence of lead on heme synthesis.27tPP 2l] 2 2) Lead may increase the inhibition of ALA-D in erythrocytes, shorten erythrocyte life span, and produce reticulocytosis or anemia.. ~ ~t It may also increase hypertension and vascular disease.~i Lead is stored in the body and has effects related to its storage or its release. 12 Deposition occurs in soft tissue and bone tissue--predominantly in the flatter. Effects may occur in those tissues, but often occur systemically on release of deposited lead or when the body burden becomes too great.- Release may be caused by acidosis or fractures. The lead in the soft tissues causes enzyme inhibition, 12 which in turn can lead to interactions of toxins.. Mercury is a general sensory irritant. It may produce skin burns, 2 rash, 22 excessive perspiration, easy blushing, partial loss of scalp hair, 22 or a decrease in hearing. It can affect taste,

305 ana it produces irritation in the mouth. 22 Mercury poisoning may affect the sense of touch, owing to the swelling of all extremities, including ears and nosegay Except for spills of inorganic mercury and excessive use of mercury-based paint, it is debatable whether indoor concentrations of mercury are ever high enough to produce those effecters This chapter deals with the biologic responses to specific pollutants and biologic agents. The pollutants discussed are sidestream cigarette smoke, radon progeny, mineral and vitreous fibers, formaldehyde, and products of indoor combustion (predominantly carbon monoxide and nitrogen oxides). Gases not usually found indoors in moderate or high concentrations--suab as sulfur oxides and ozone--are not discussed at length. Nor are sources like cooking, which may produce some particles or hydrocarbons, but about which little is known. For information on substances that are known to have adverse effects in the occupational environment or on solvents, dusts, etc., which have been reviewed thoroughly, the reader is referred to the published literature (e.g., reports issued by FDA and CPSC). Environmental factors that are not known to have adverse biologic Impact are not discussed here; rather, there are appropriate references to other chapters. CES 7. 1. Angle, C. R., and M. S. McIntire. Environmental lead and children: The Omaha study. J. TDxicol. Environ. Health 5:855-870, 1979. 2. Berkout, P. G., N. J. Paterson, A. C. Ladd, and L. J. Goldwater. Treatment of skin burns due to alkyl mercury compounds. Arch. Environ. Bealth 3:592-593, 1961. Bull, R. J. Effects of trace metals and their derivatives on the control of brain energy metabolism, pp. 425-440. In S. D. Lee, Ed. Biochemical Effects of Environmental Pollutants. Ann Arbor, Mich: Ann Arbor Science Publishers, Inc., 1977. Dahlgren, O. Aboominal pain in lead workers. Arch. Environ. Health 33:156-159, 1978. 5. Daines, B. H., D. W. Smith, A. Feliciano, and J. R. Trout. Air levels of lead inside and outside of homes. Ind. Med. Surg. 41~107:26-28, 1972. 6. DuBoi=, K. P. Interactions of chemicals as a result of enzyme inhibition, pp. 95-107. In D. H. R. Lee, and P. Kotin, Eds. Multiple Factors in the Causation of Environmentally Induced Disease. New York: Academic Press, Inc., 1972. Elinder, C.-G., T. Kjellstrom, L. Friberg, B. Lind, and L. Lineman. Cadmium in kidney cortex, liver, and pancreas from Swedish autopsies. Arch. Environ. Health 31:292-302, 1976. 8. Finelli, V. N . Lead, zinc, and 6-aminolevulinate dehydratase, pp. 351-363. In S. D. Lee, Ed. Biochemical Effects of Environmental Pollutants. Ann Arbor, Mich.: Ann Arbor Science Publishers, Tnc.,- 1977. 9. Foote, R. S. Mercury vapor concentrations inside buildings. Science 177:513-514, 1972.

306 10 . Goldberg, A. M. Neurotranamitter mechani - s in inorganic lead poisoning, pp. 413-423. In S. D. Lee, Ed. Biochemical Effects of Environmental Pollutants. Ann Arbor, Hich.: Ann Arbor Science Publishers, Inc., 1977. 11. Goldsmith, J. R., and L. T. Friberg. Effects of air pollution on human health, pp. 457-610. In A. C. Stern, Ed. Air Pollution. 3rd ed. Vol. II. The Effects of Air Pollution. New York: Academic Press, Inc., 1977. 12. Hayes, W. J., Jr., R. A. Neal, and H. H. Sandstead. Role of body stores in environmentally induced disease - DOT and lead, pp. 136-164. In D. lI. R. Ice and P. Kotin, Eds. Multiple Factors in the Causation of Environmentally Induced Disease. New York: Academic Press, Inc ., 1972. 1 3. He rnberg , S . Lead , pp. 715-?69 . In C. Zenz , 3 :d ., In Occupational Medicine. Principles and Practical Applications. Chicago: Year Book Medical Publishers, Inc., 19770 14. Hirschman, S. Z., M. Feingold, and G. Boylen. Mercury in house paint as a cause of acrodynia. Effect of therapy with N-acetyl-D,L- penicillamine. N. Engl. J. Hed. 269: 889-893, 1963. 15. Joselow, M. M. Indoor air pollution by Mercury. Ann. Intern. Hed. 78:449-450, 1973. Kass, E. B. Multiple factors in the causation of renal disease, pp. 83-91. In D. B. K. I`ee and P. Kotin, Eds . Multiple Factors in the Causation of Environmentally Induced Disease. New York: Academic Press Inc., 1972. 17. Morse, D. L., W. N. Watson, J. Bousworth, L. E. Witherell, and P. J. Landrigan. Exposure of children to lead in drinking water. Am. J. Public Health 69: 711-712, 1979. 18 . Needleman , ~ . L., C . Gunnoe , A. Leviton , R. Reed , ~ . Peres3.e . C . 16. . Maher, and P. Barrett. Deficits in psychologic and classroom performance of children with elevated destine lead levels. N. Engl. J. Med. 300: 689 - 695, 1979. 19. Petering , H. G., L. Murthy, and F. L. Cerklewski. Role of nutrition in heavy metal toxicity, pp. 365-376. In S. D. Lee, Ed. Biochemical Effects of Environmental Pollutants. Ann Arbor, Mich.: Ann Arbor Science Publishers, Inc., 1977. 2 0 . Reels, B., J. -P. Buchet, R. "uwerys, G. Bubermont , P. Brusux , F. Claeys-Thoresu, A. "fontaine, and J. Van Overechelde. Impact of air pollution by lead on the heme biosynthetic pathway in school-age children. Arch. Environ. Bealth 31:310-316, 1976. 21. Schanker, L. S. Flow of environmental agents in reaching their site of action, pp. 6-14 . In D. B. X. Lee, and D. Hinard, Eds. Physiology, Environment, and Man. New York: Academic Press Inc., 1970. 22. Sexton, D. J., K. E. Powell, J. Liddle, A. Smrek , J . C . Smith, and T. W. Clarkson. A nonoccupational outbreak of inorganic mercury vapor poisoning. Arch. Environ. Bealth 33 :186-191, 1978. 23 . Shy, C., J. Goldsmith, J. Hackney, M. D. Lebowitz , and D. Henzel . Statement on the Health Effects of Air Pollution: ATS News 4:22-62, Spring, 1978.

307 24 . Stokinger, B. E. Means of contact and entry of toxic agents, pp. 7-11. In W. M. Gafafer, Ed. Occupational Disease-: A Guide to Their Recognition. U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1097. Washington, D.C.: U.S. Government Printing Off ice, 1964 . 2 5. Stok inger, H . E: . Mode of action of toxic substances, pp. 13-26 . In W. M. Gafafer, Ed. Occupational Diseases: A Guide to Their Recognition. U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1097 . Washington, D.C.: U. S . Government Printing Of f ice, 1964 . 26. Ter Haar, G. An investigation of elevated blood lead levels in Detroit children. Arch. Environ. Health 34:145-150, 1979. 27 . Waldbott, G. L. Health Effects of Environmental Pollutants . Saint Louis: The C. V. Mosby Company, 1973. 316 pp. 28. World Health Organization. Health Hazards of the Human Environment. Geneva: World Health Organization, 1972 . 387 pp. RADON AND RADON PROGENY The physical, chemical, and radiologic properties of radon-222 (referred to as radon), radon-220 (thoron), and their progeny and the principles of dosimetry are summarized in Chapter nl. The unit of exposure of man is the working level (WL), def ined as the quantity of short-lived progeny that will result in 1.3 x 105 Rev of potential alpha energy per liter of air. This is equivalent to a concentration of short-lived radon progeny in complete equilibrium with radon-222 at 100 pCi/L in air. The working-level month (WLM) in a term defined originally for occupational exposure, and 1 WLM is exposure at 1 Wl' for 170 h. Thus, the working-level month is a measure of cumulative exposure. The working level is a measure of exposure rate; it has been widely assumed that, over a 70-yr lifetime, typical total-lifetime background exposures are in the range of 5-20 WLM. However, the average and distribution in the United States are not well studied. Some restrictions on the use of the working level must be noted. First, it i. not useful for thoron progeny, because the~dose delivered to the bronchial epithelium for the same amount of potential alpha energy (1.3 x 105 MeV) per liter of air can be much higher than that of radon progeny. Second, characterization of the dose to lung airways based solely on the working level involves a degree of uncertainty: the distribution of the lung dose depends on the unattached fraction, the particle size distribution of the aerosol to which the radon progeny are attached, lung morphometry, breathing rate, etc. Even with a general knowledge of the physical factors, other uncertainties in calculating dose are sufficiently great that characterization of ache exposure atmosphere in terms of any measure more precise than working level is inappropriate for dose approximation: . The difficulties in characterizing dose and relating it to effects have been reviewed recently by Cross et al. ~. It should be noted that deviations in the exposure environment f rom reference conditions may result in actual

308 lung doses that differ fro. those expect" on the basis of the reference condition e assumed. REVI" OF DOSE AND EXPOSURE cAL`:uLATIoals The inhalation of radon progeny leads to a very inh~geneous alp" dose to the human lung. For a variety of reasoner-including preferential deposition, mucociliary clearance of aerosols deposited on conductive airways. and the observed tumor sites and types it is believed (but by no means certain) that the radiation from the alpha-particle irradiation of the basal cells of the upper bronchial epithelium is the exposure characteristic cost closely relatable to carcinogenic risk. However, it is difficult to determine the alpba-particle close, because of the intractable difficulty of measuring it _ vitro. Bence, dose calculations bate been based on physical and biologic models. Dosimetric models have been developed for adults and Eve been satirized in several recent report. 3~ ·5 ·~ Ad'' -- ~e''~.y ~ in' ase~dePendent model was developed by ~fasnn et al. ~ ' Moreover. the reference at-~spbere is important for dose calculations, which are influenced by the fraction of unattached progeny and the particle size distribution of the progeny. Breathing rate, au~octliery clearance, lung aorpho~etry, age, and sex aust also be considered. Depending on assumptione about the equilibrium, unattached fraction of progeny, carrier aerosol distribution, and the locus of target cells chosen for the estiastes, calculated dose estimates per working-level aontb can vary by up to a factor of 100. A comprehensive evaluation of the dose through the various regions of the lung, taking into account attached and unattached fractions and particle size distributions, has recently been publiabed. 2 2 The table of background dose rates cited in Chapter IV is taken fro National Co~ission on Radiation Protection and Measure~sents {NCRP) Report 45, which assumes that the reference exposure atmosphere for the United States is at about the concentration found in outdoor sir, assumed to be radon-222 at 150 pCi/~3 in equilibrium with the progeny. George and Brealin ~ ~ measured radon working levels in cellars, fires-floor spaces, and outdoors for 21 houses in Hew York and flew Jersey and found the ratio of firat-floor to outdoor average Annual radon content to be 4.6, with median outdoor content of 180 pCt/a . The firat-floor-to~outdoor waricing-level ratio was lower, 2.6' that suggeeto a reduced equilibrium indoors, as eight be expected. The annual Dean on the first floor Wee 0.004 if*. Bow representative these are of the metropolitan Hew York area or other areas is rot known. On the assu~tion that there was an 808 o`:cupancy factor in the houses, with the 201 balance spent outdoors, the annual weighted estimate for the New York-New Jersey study was 0.11 HTM~/yr. Over 70-yr life, that would produce roughly 8 Em.

309 BIOLOGIC EFFECTS This section deals with the estimation of potential risk to On from inhalation exposure to radon progeny, the basis for the estimates of risk, and the shortcomings in our knowledge related to the exposures normally encountered. Underground Miners Much of our knowledge about the human health effects of radon and its progeny is based on the experience of underground miners whose exposures must be charac~cerized, in relation to environmental characteristics, as having high dose rates (working levels ~ and high cumulative doses (working-level months). Table VII-1 shows representative values for underground mines and typical indoor measurements in houses, to provide perspective or. the use of the term ~high. ~ In the general population, exposure to radon progeny occurs under conditions rather different from those in underground mines, and it is therefore necessary to consider the extent to which epidemiologic studies in miners are germane to the general population. The feasibility of conducting epidemiologic studies of nonmining populations has recently been examined, and populations of health-spa workers were identified as promising.4' There have been five major reviews of results of studies on underground miners. The analysis here draw" partly on those and on the reports cited in them. All five reviews dealt with underground-mininq experience and with miners who were, for the most part, adult males. Conclusions patterned after those of Seltser derived from those studies are as follows: · There is no reason to doubt an excessive lung-cancer risk among the early Bohemian uranic miners in Schneeberg and Joachimatal, I' the U.S. uranium-miners at the Colorado Plateau, 27 and Czechoslovakian uraniu~miners. 2 ~ ~ ~ In addition, there were increased occupational lung-cancer rates, relative to those of equivalent smoking groups in the general population, among underground miners with large exposures to radon and progeny in hematite, fluorapar, and zinc miner in several countries. " · It is clear that the respiratory tracts of the uranium-minere received massive exposure from the alpha-emitting progeny, which are responsible for much more of the radiation exposure than the parent radon itself. · There appears to be no convincing evidence that there are any other components of the mine environment that are responsible for the excess lung-cancer risk . Conversely, there is no evidence to rule out a contributory role of other components of this unusual environment, i.e., respirable silica dust and variable background dust concentrations and size distributions.

310 . TABLE VI I-1 Reprelentat ive Exposures to Radon-222 Progeny Sub Sects or Location Uranium minersC Outdoors Indoors wLa WIMa fib 1-20 100~10, 000 <O. 001 - _ <0.01 10 aTo nearest order of magnitude. bLifetime or duration of exposure. CIncludes exposure before ~d-1960s .

311 · There has been no definitive study in which a valid comparison group for the highly selected occupational populations was used. The observed-to-expected ratios have generally been expressed in relation to the general population or to a selected portion of the general population, and not to other underground miners. Such a comparison may be difficult to obtain, because most underground mining involves exposure to radon progeny at a higher-th.an-background concentration. · Cigarette-smoking is clearly important, but not essential, in the induction of lung cancer. Lung cancer is greatly increased in these studies among uranium-miners who smoke, but is also higher among non-cigarette-smoking miners. Inferences from both the human epidemiologic work and the animal toxicologic studier are contradictory: in each case, one can cite opposite conclusions on the impor tance of smok ing . Fundamentally, the existing information is insufficient for a decision of whether radiation exposure multiplies the risk of lung cancer associated with other factors, such as smoking, or whether it produces a cancer risk that is proportional to the radiation exposure and merely additive to these other risks. In this review, a model based on the latter idea, the Absolute-risk model,. has been adopted, although it must be kept in mind that it may not represent the true situation. I' Epidemiologic studies of carcinogenesis may be considered complete if all the population at risk has died and the follownp is complete. Thus what is usually measured is some cumulative tumor incidence in the population up to the time of the analysis, which is lower than the 1 if etime excess r isk . For such data, r isks may be def ined as cumulative incidence to time t f rom exposures X . Or one may try to express the r isk in terms of appearance per unit time (usually years), being careful to define the period over which tumors appear. One must distinguish between latent period and followup time of the study group. Sometimes, average risk per year is found by dividing cumulative incidence to time t by the followup time (i.e., as is done by UNSCEAR.S); but recently the National Research Council Committee on the Biological Effects of Ionizing Radiations (the BEIR Committee) excluded the latent period to define the risk per year. Thus, risk estimates (in cancers/106 person-years per WLM) should not be directly compared with other dimensionally equivalent risk estimates found for a different Period. The method chosen here uses the cumulative incidence divided by the followup time . In any event, the time over which a tzme-dependent r isk estireate is derived is always specif led. The results of studies of lung cancer in underground uranium-miners in the United States and Czechoslovakia and non-uran~um-:niner" in Sweden, Canada, and the United Kingdom, analyzed as a linear, no~threshold phenomenon, are summarized in Table VII-2. The first column shows the excess r is k In Terms of the number of expected lung-cancer cases per working-level month per year; these range between 2.2 x 10-6 and 8 x ~ 0 6 . Column 1 is obtained by dividing the observed number of lung cancers in the study group by the followap time

312 ~ Y _ ~ ~ _ o o _ ~ o C o o sly =4' C ~ J C-) L) I I, ted ; dU .1 ° ~ ~ ~ ~ 80 O 1 t 1 1 1 v f t | /° V ,x, ~ ~ O t 1 1 I K v ~ ' C| e c 0 " ~ ~ 1 ~ C C o c t: ~ a ~ :) 1 ~ ~ ~ Cal ,, ~ 31 X X 8 ~ · O O ~ 3 X g 1 ~ ~ 1 1 1 In _ ~ ~ AL . ~ ~ ~ . o ~ ~ lo I J O ~ ~ I 0` —~ I t I E~ :^ 1 — ~ 1 1 1 _ ~: ~ ^3 0 o0= _ C ~ ~ . 3 _. O - 10 to ~ ~ ~ : JO 4~` t8 ·O ~ 10 0 ~ ~ 8 . , , ~ ~ ~ 1 C c~ O 0 - 0 ~ ~ 3 X ~ — X ~ _ ~ ~ 3 0 0 _' eo_ K ~ ~ ~ ~C ~ :: . 0 ~ ~ ~J ~_ ~ J ~ ~0 1 1 O O ~0 o K K O ~ ~

313 in years and the average exposure of the population. The second column show. the follownp time of the study in years. These studies in general have not followed the exposed populations until the end of life . Therefore, a valid estimate of the cumulative risk to the end of life cannot be derived from these studies. Column 3 is an under- estimate of lung-cancer risk to the end of life. Indeed, UNSCEAR. s has suggested that, beyond 15 yr of exposure, the r isk per working- level month per year decreases from 4 x 10 6 to 2.2 x 10 6 up to 25 yr of exposure. UNSCEAR has suggested that the cumulative lifetime lung-cancer risk among these miners might be as high as 200 x 10-6 or 4 50 x 10-6 per work ing-le~rel month . In the study of Czechoslovakian miners, Kunz et al. 2 ~ found that the proportion of cigarette-smokers in the underground miners was about 70%, roughly equal to the proportion in their general male population, and concluded that the r isk increases with age at onset of exposure . A more recent reanalysis of the data from the uranium-miners in the Colorado Plateau done by Lundin et al. 26 concluded that the risk increased progressively from nonsmokers through light to heavy cigarette-smokers, but the excess r isk over that to nonminers with equivalent smoking was much less for nonsmokers and was about the same for light and heavy smokers. Lundin et al. further suggested that -amok ing promotes the appearance of lung tumors and thus that lung cancers appear earlier in smokers than in nonsmokers . If true, this would effectively result in a lower cumulative incidence in nonsmokers. Saccomanno et al. (personal co~ranunication), in analyzing ages of smokers and nonsmokers among 302 Colorado Plateau miners with lung cancer, found the average age at death to be earl ier in the nonsmoker s 48. 5 yr ~ than in the smokers (56 . 5 yr ~ . Thus, the risk estimates shown in Table VII-2 seem to cluster in two groups, 2.2 x 10 6 to 3.4 x 10-6 WLM/yr in the U.S. uranium- miners and the Swedes and f luorspar-miners and 3-4 times higher in the Czechoslovakians and iron-miners. The physical measurements of mine atmospheres in the U. S. and Czechoslovakian studies have not been compared, although systematic error" exceeding 50% seem unlikely (Domanski, personal communication). The reason for the higher risk among the Czechoslovakian miners is not clear. Lundin et al. 2 ~ suggested that they may be higher because Czechoslovakian miners started mining at younger ages. This hypothesis Is not consistent with the observed dependence on age for equal doses · · In animals. Thus, the risk estimates differ between the various studies by a factor of 3 or more for linear, absolute-risk estimates. However, g rester uncertainties are involved in extrapolating to lower exposures in the range below 100 WLM, and further uncertainties are involved in extrapolating to populations with a wide distribution in ages. The question of the influence of age and gender on effect is not yet settled in either experimental animals or man. Archer ~ has recently plotted his evaluation of the excess annual risk per working-level month (i.e., that above the risk established for the control population ~ for lung cancer versus the estimate of cumulative work ing-level months . This is reproduced in slightly

314 modified form in Figure VI]-1. The risk per working-level month increases monotonically down to several hundred working-level months. Although the reliability of the individual points is poor, the fact that all are well below the maximum is highly suggestive. Histologic and CYtosenetic Studies in Man--Lung Cancer Exposure to radon and thoron progeny has been shown to be correlated with chromosomal aberrations measured in peripheral blood lymphocytes. 12 33 In uranium-miners, there appears to be a good correspondence between increased prevalence of chromosomal aberrations and cytologic sputum changes characteristic of markedly atypical cells and carcinomas _ situ.' On the basis of pathologic examination of 52 lung cancers in uranium-miners in the Colorado Plateau, Saccomanno et al. in i964 reported that there was a predominance of small-cell undifferentiated carcinoma,' and in 1971 150 cases were evaluated by a panel of pathologist", who came to the same conclusion. 3 S An interesting conclusion of this group was that the mean latent period for the small-cell types in miners with fewer than 700 WLM was 9.4 ye, compared with mean latent periods of 17.8 yr for all cancer types for exposure greater than 700 WLM. The prevalence of the small-cell type seems to be decreasing with time, from 76% (13 of 17) in the period 1954-1959 to 22% (13 of 58) in the period 1975-1979 (Saccomanno, personal communication). The meaning of this is unclear, although the small-cell type of cancer may be associated with the higher dose rates (in working levels) of the 1950s and early 1960s in uranium mines in the Colorado Plateau. Archer et al., analyzed lung cancer by type in a study group of 3,366 uranium- miners between 1950 and 1970 and found 66 small-cell cancers, compared with two expected. Saccomanno et al. 3? have shown that an early indicator of both precancerous lesions and carcinoma of the -king can be obtained by cytologic examination of cells from the sputum; this offers the opportunity to identify persons at risk early and to provide early treatment. Auerbach et al. ' have made detailed histologic examinations of lungs of uranium-miners and nonmining controls matched for age and Invoking history obtained at autopsy. They concluded That the synergistic effect of the exposure to uranium dust along with cigarette smoking increases the risk of lung cancer and that in addition to a main tumor mass, other sites of tissue alterations leading to tumor development are frequently already present in the lung.# In epidemiologic studies in nonminers, Hess et al.20 have demonstrated a correlation between high radon concentrations in well water in Maine and mortality from lung cancer and all cancers, on the bands of available vital statistics. There were no controls for smoking. The lung-cancer incidence in Tine is lower than the national incidence, and a def initive analysis of the relationship of radon in water and long-term radon concentration in indoor air was not presented. These studies should be followed up with detailed

315 U) G C) z Z. 35 _ 30 25 20 J J J 3 ~ ~ ~5 o cc_ 10 _ ~ to ~ z o o . _ · to o a O Sweden (protactinium, zinc, irony O Czechoslovakia (uranium} United States (uranium) · Canada (uranium) · United Sow (White rural nonsmokers) · Schn~burg—Joachimsthal Canada (Iluorsper) o I I I A o ,.\ O ~ I t 1 1 1 1 1 ~ _1 100 200 300 400 500 600 700 1200 or more {0.35} (0.71} {1.11 {1.4} (t.8} {2.1) (2.51 44 or more) CUMULATIVE WLM (Mean Exposure Rate, WL) FIGURE VI I-1 Attributable lung cancer per unit of radiation from radon progeny as function of cumulative exposure and exposure rate. Adapted from Archer.

316 case-contr=1 studies in which the long-term radon concentrations in air are carefully evaluated. Axelson et al. ~ conducted a case-control study based on death certificates and housing types in Sweden and concluded that there may be a relationship between housing type and lung cancer. Residence in stone houses was score common among those with lung cancer than residence in wooden houses. No exposure data on radon or radon progeny were correlated, nor was information available on heating and cooking practices . Although both studies suggest a link between radon exposure and lung cancer, neither is sufficient to suggest causality. Inhalation-Toxicology Studies in Animai8 Experimental studies in animals offer the opportunity to test hypotheses related to the effects of smoking on animals and whether smok ing is additive or synergistic in inducing or accelerating the appearance of lung cancer . Until recently, lung cancers had not been produced with radon progeny in animal.. Early experiments with very large exposures showed no ~hort-term effects on the lung, and, although dogs were exposed, the negative short-term pathologic results discouraged the pursuit of such studies in the United States until recently. Studies of carcinogenesis of radon progeny are being conducted in France by researchers at CEAii and in the United States at the Battelle Pacific Northwest Laboratory. ~. Short-term exposures conducted at the University of Rochester showed little pathologic change in lungs of dogs for short followup times (D. Morken, personal communication ~ . There has also been work on lung carcinogenesis after intratracheal instillation or inhalation of long-lived alpha-emitters. Those studies in which exposures are primarily of the pulmonary regions of the lung, rather than of the bronchial airways, are not considered relevant. The combined effects of smoking and inhalation of uranium-ore dust, radon progeny, and diesel-engine exhaust have been studied in Syr fan hamsters and dog=. Is One conclusion we" that the Syrian hamster was not an appropr late animal model for the study of pulmonary carcinogenesis, inasmuch as it appeared to be resistant to carcinoma induction by realistic exposures in lifespan exposure studies. Information obtained with beagles was useful, although limited. Four groups of 20 dogs were studied. All animals with lung tumors had cumulative exposures greater than 13,000 WLM. It was observed that smoking decreased the number of observed tumors . The tumors in uranium-miners are in the smaller bronchi, whereas in animals they are bronchioalveolar and in the nasal epithelium. It was suggested from this study that the human and animal data are not directly comparable. However, it is to be expected that the morphometric differences between animals and man and differences in exposure conditions will change the relative sites of particle deposition, the cell types being irradiated most heavily, and the loci and cellular origin of tumorse

317 Complementary studies were done in France with rodents exposed to radon progeny with and without concurrent exposure to other substances. ~ ~ This very extensive program of studies on lung tumorigenesis in the rat demonstrates that it is a suitable model for come aspects of radon-progeny tumor igenes i s in the lung . The tumor ~ that are examined in his~copathologic studies at death appear very late in life , grow slowly (relative to the rat 's life span), and are rarely f atal . 2 ~ The data on rodents indicate a cumulative incidence per working- level month that is rather similar to that estimated for man, even though the tumor types and sites in rodents differ considerably from those found in humans. The pathologic basin for this and the comparability have been discussed elsewhere. ~~ Similar studies of rats are underway at Battelle-Pacific Northwest. There are not yet complete; exposure began later than in the French studies. Because lung tumors in rodents show up after the median life span and are therefore restricted to less than half the population at risk, it is premature to speculate on the eventual results of the studies ~. and their relationship to the French studies. SUM ARY AND CONCLUSIONS There is no doubt that radon and its progeny in sufficient doses can produce lung cancer in man. I t is also generally believed, on the basis of dosimetric considerations, that the short-lived progeny are responsible for most o f the lung-cancer r isk . Some epidemiologic studier of underground miners have suggested that smokers seem to be at higher risk of lung cancer than nonsmokers, but the r isk to nonsmokers is also increased . Whether the ~ isks are additive or synergistic is not yet clear. The cumulative exposures (in working-level months) at which human and animal carcinogenesis has been observed are generally higher by an order of magnitude or more than those characteristic of the normal indoor environment. Excess cancers have been seen in association with exposures that were 2-3 order" of magnitude greater than those found in normal indoor environments. Thus, to predict the results of the effects of decreased indoor ventilation on exposure to radon progeny, it is necessary to extrapolate beyond the range of exposures for which ef feats have clearly been documented. Although the generally accepted linear dose-response function does not fit the available data very well, there is no established alternative dose-response function. We can conclude that dose rate or fractionation has an effect that cannot yet be adequately described. Only by a combination of human, animal, and cellular studies will it be possible to estimate with any confidence the risk coefficients for natural indoor exposures in the range of interest, as enhanced by low air turnover associated with energy~conservation efforts.

318 Although there are legitimate reasons to criticize it, the working-level month is probably the best available measure of potential dose as related to likely biologic effect. Its use should be judicious. REFERENCES S. 9. 12. 1. Archer, V. E. Effects of Low Levels of Radon on Man. Paper presented at the Specialist Meeting on Assessment of Radon and Daughter Exposure to Man and Related Biological Effects, Rome, 1980. 2. Archer, V. E. Factors In expo~ure-response relationship" of radon daughter injury, pp. 324-367. In Conference/Workshop on Lung Cancer Epidemiology and Industrial Applications of Sputum Cytology. Golden, Colo: Colorado School of Mines Press, 1979. 3. Archer, V. E., G. Saccomanno, and J. H. Jones. Frequency of different histologic types of bronchoqenic carcinoma as related to radiation exposure. Cancer 34:2056-2060, 1974. Archer, V. E., J. K. Wagoner, and F. E. Lundin, Jr. Cancer mortality among uranium mill workers. J. Occup. Med. 15:11-14, 1973. Archer, V. E., J. R. Wagoner, and F. E. Lundin. Lung cancer among uranium miners in the United States. Health Phys. 25: 351-371, 1973. Archer, V. E., J. K. Wagoner, and F. E. Lundin, Jr. Uranium mining and cigarette smoking effects on man. J. Occup. Med. 15:204-211, 1973. Auerbach, O., G. Saccomanno, M. Kuschner, R. D. Brown, and L. Garfinkel. Histologic findings in the tracheobronchial tree of uranium miners and non-miners with lung cancer e Cancer 42:483-489, 1978. 8. Axelson, O., C. Edling, and H. filing. Lung cancer and residency-- A care referent study on the possible impact of exposure to radon and its daughters in dwellings. Scand. J. Work Environ. Health 5:10-15, 1979. Brandom, W. ~ ., G. Saccomanno, V. E. Archer, P . G. Archer, and A. O. Bloom. Chromosome aberrations as a biological dose—response indicator of radiation exposure in uranium miners. Radial. Res. 76: 159-171, 1978 . 1 0 . Budnitz , R. J ., J . V. Berk , C . D. Bollowell , W. W. Nazarof f , A. V. Nero, and A. H. Rosenfeld. Human Disease From Radon Exposures: The Impact of Energy conservation in Residential Buildings. Lawrence Berkeley Laboratory Report LiBL-7809, Revised EEB-Vent-78-5 . Berkeley, Cal .: r,awrence Berkeley Laboratory, 1979. 11. Chameaud, J.' R. Perraud, R. Masse, and J. Lafuma. Cancers induced by 2 2Radon in the rat. Paper presented at the Specialist Meeting on Assessment of Radon and Daughter Exposure and Related Biological Effects, Rome, 1980. Costa-Ribeiro, C., M. A. Barcinski, N. F~gueiredo, E. Penna, F. Booboo, N. Logo, and H. Rrieger. Radiobiological aspects and radiation levels associated with the mill ing of monaz ite sand . Health Phys . 28: 225-231, 1975.

319 13. Cross, F. T. Exposure standards for uranium mining. Bealth Phys. 37:765-772, 1979. 14. Cross, F. T., R. F. Palmer, R. H. Busch, and R. L. Buschbom. Influence of Radon Daughter Exposure Rate and Uranium Ore Dust Concentration on Occurrence of Lung Tumors. Paper presented for Battelle Pacific Northwest Laboratories at the Specialist Meeting on Assessment of Radon and Daughter Exposure and Related Biological Effects, Rome, 1980. 1 5 e Cross , F. T., R. F. Palmer , R. E. Filipy, R. lI . Busch , and B. O. Stuart. Study of the Combined Effect" of Smoking and Inhalation of Uranium Ore Dust, Radon Daughters and Diesel Oil Exhuast Fumes in Hamsters and Dogs. Final Report. Battelle Pacific Northwest Laboratories Report No. PNL-2744-UC-48. Washington, D.C.: U.S. Department of Energy, 1978 . 143 pp. l 5a . Eadie, G. G ., R. F. Kaufmann , D. ~ . Markley , and R. Williams . Report of Ambient Outdoor Radon and Indoor Radon Progeny Concentrations dur ing November 1975 at Selected Locations in the Grants Mineral Belt, New Mexico. U.S. Environmental Protection Agency, Of f ice of Radiation Programs Report NO. ORP/LV-76-4 . Las Vegas: U. S . Environmental Protection Agency, Las Vegas Facility, 1976. S3 pp. 16. Federal Radiation Council. Guidance for the Control of Radiation Hazards in Uranium Mining. Staff Report No. 8. Revised September 1967. 17. Fisher, D. R. Estimating Population Health Risk from Low-Level Environmental Radon. Paper presented for Battelle Pacific Northwest Laboratories at the Specialist Meeting on Assessment of Radon and Daughter Exposure and Related Biological Effects, Rome, 1980 . 1 7a . Fitzgerald , J . E., Jr ., R. -J. Guimond, and R. A. Shawl A Preliminary Evaluation of the Control of Indoor Radon Daughter Levels in New Structures. U.S. Environmental Protection Agency Report No. EPA-520/4-76-018 . Washington , D.C.: U.S. Environmental Protection Agency, Off ice of Radiation Programs, 1976. 88 pp. 18 . George, A. C., and A. J. Breslin. The distribution of ambient radon and radon daughers in residential buildings in the New Jersey-New York area, pp. 1272-1292 ~ includes discussion) . In T. F. Gesell and W. M. I,owder, Eds. Natural Radiation Environment III. Vol. 2. Proceedings of a Symposium Held at Houston, Texas, April 23-28, 1978. Oak Ridge, Tenn.: U.S. Department of Energy, Technical Information Center, 1980. 19. Gui~ond, R. J., Jr., W. B. Ellett, J. E. Fitzgerald, Jr., S. T. Windham, and P. A. Cuny. Indoor Radiation Exposure Due to Radium-226 in Florida Phosphate Lands. U.S. Environmental Protection Agency (Office of Radiation Programs) Report No. EPA 520/4-18-013. Washington, D.C.: U.S. Government Printing Office, [2061 pp. 20. Hess, C. T., S. A. Norton, W. F. Brutssert, R. E. Casparius, E. G. Coombs, and A. L. Best. Radon-222 in potable water supplies in New England. J. N. Engl. Waterworks Assoc. 94:113-129, 1980.

320 21. Bofmann, W., S. Steinhiualer, and E. Pohl. Age-, sex-, and weight~dependent dose patterns due to inhaled natural radionuclides, pp. 1116-1144. In T. F. Gesell and W. M. Lowder, Eds. Natural Radiation ltn~rironment III. Vol. 2. Proceedings of a symposium Held at Houston, Texas, April 23-28, 1978. Oak Ridge, Tenn.: U.S. Department of Energy, technical Information Center, 1980. Jacobi, W., and K. Eisfeld. Dose to tissues and effective dose equivalent of radon-222, radon-220 and their s~rt-lived daughters. Institut fur Strahlenschutz der Gesellechaft for Strshlen und Unweltforeebung non, 1980. Johnson, R. B., Jr., D. E. Bernhardt, H. S. Nelson, and B. H. Calley, Jr. Assessment of Potential Radiological Bealth Effects from Radon in Natural Gas. U.S. Environmental Protection Agency Report No. EPA-520/1-73-004. Washington, D.C.: U. S. Envirormentel Protection Agency, Office of Radiation Programs, 1973. 68 pp. Kunz, E., J. tic, V. Placek, and J. }Ioracek. Lung cancer in man in relation to different time distribution of radiation exposure. Bealth Phys. 36: 699-706, 1979. 2 5 . Ietourneau , E. G ., and ~ . T. Wigle . Mortality and Indoor Radon Daughter Concentration'; in 13 Canadian Cities. Paper presented at the Specialist Meeting on Assessment of Radon and Daughter Exposure and Related Biological Effects, Bane, 1980. 2 6. Lundin, F. E., Jr ., V. E. Archer , and J. R. Wagoner . An exposure-tme-response model for lung cancer mortality in uranium miners: Effects of radiation exposure, age, and cigarette ~king, pp. 243-264. In Proceedings of S"s Conference on Energy and Bealth, 1978. 2 7 . Lundin , F . E ., Jr ., J . R . Wagoner , and V . E. Archer . Radon Daughter Exposure and Respiratory Cancer: Quantitative and Temporal Aspects. National Institute for Occupational Safety and Health, and National Institute of Environmental Bealth Sciences Joint Monograph No. 1, 1971. 175 pp. 28. Masse, R. Histogenesis of lung tumors induced in rats by inhalation of alpha emitters, pp. 498-52}. DOE Symposium Series 53, CONF 79 10002. Washington, D.C.: U. S. Department of Energy , 22. 23. 24. 1979. 29. ens, M., J. B. Lindstrom, C. E. Dungey, and W. E. Kisteleski. Radon and Radon-Daughter Concentrations in Air in the Vicinity of the Anaconda Uranium Hill. U.S. Nuclear Regulatory Co~ission Report No. NUR=/CR-1133. Washington, D.C.: U. S. Nuclear Regulatory Commission, Office of Nuclear Regulatory Research, 30. _ 1979. 97 pp. National Research Council, Committee on the Biological Effects of Ionizing Radiations. The Effects on Populations of Exposure to pow Levels of Ionizing Radiation: 1980, pp. 308-331. Washington, I'.C.: National Academy Press, 1980. 31. National Research Council, Advisory Committee on Biological Effects of Ionizing Radiations. The Effects on Populations of Exposure to Low Lie~rels of Ionizing Radiation, pp. 145-157. Washington, D.C.: National Academy of Sciences, 1972.

321 32. Pohl-Ruling, J., and P. Fischer. An Epidemiological Study on Chromosome Aberrations in a Radon Spa. Paper pre~en~ced at the Specialist Meeting on the Assessment of Radon and Daughter Exposure and Related Biological Effects, Rome, Italy, March 3-7, 1980 . 33. Pohl-Ruling, J., and P. Fischer. The dose-effect relationship of chromosome aberrations to a' and ~ irradiation in a population subjected to an increased burden of natural radioactivity. Cadet. Res. 80 :61-81, 1979. 34. Royal Commission on Health and Safety of Miners (Ontario}. Report of the Royal Commission on Health and Safety of Workers in Mines. Toronto, Canada: Province of Ontar lo, Ministry of Attorney General, 1976. [349] pp. Saccomanno, G., V. E. Archer, O. Auerbach, M. Kuschner, R. P. Saunders, and M. G. Klein. Histologic types of lung cancer among uranium miners. Cancer 27:515-523, 1971. 36. Saccomanno, G., V. E. Archer, O. Auerbach, R. P. Saunders, and L. M. Brennan. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 33:256-270, 1914. 37. Saccomanno, G., V. E. Archer, R. P. Saunders, O. Auerbach, and M. G. Klein. Early indices of cancer risk among uranium miners with reference to modifying factors. Ann. N.Y. Acad. Sci. 271:377-383, 1976. 38. Saccomanno, G., V. E. Archer, R. P. Saunders, L. A. James, and P. A. Beckler. Lung cancer of uranium miners on the Colorado Plateau. Health Phys. 10:1195-1201, 1964. 39. Saccomanno, G., R. P. Saunders, H. G. Klein, V. E. Archer, and L. Brennan. Cytology of the lung in reference to irritant, individual sensitivity and healing. Acta Cytol. 14:377-381, 1970. 40. Seltser, R. Lung cancer and uranium mining. Arch. Environ. Health 10:923-936, 1965. 41. gem, J., E. Kunz, and V. Placek. Lung cancer in uranium miners and long-term exposure to radon daughter products. Health Phys. 30:430-437, 1976. 42. Snihs, J. O. The approach to radon problems in non-uranium mines in Sweden, pp. 900-911. In Proceedings of the Third International Congress of the International Radiation Protection Association, Washington, D.C., September 9-14, 1973. U.S. Atomic Energy Commission Report CONF-730907-P2 . Washington, D.C.: U. S. A&comic Energy Commission, 1974. 43. Steinhausler, F., E. Pohl, and W. Mofmann. On the Suitability of Epidem~ological Studies of Population Groups Exposed to Elevated Levels of Radon and Daughters. Paper presented at the Specialist Meeting on the Assessment of Radon and Daughter Exposure and Related Biolog ical Ef fects, Rome, Italy, March 3-7, 1980. 44. Turner, J. E., C. F. Holoway, and A. S. Loebl, Eda. Workshop on Dosimetry for Radon and Radon Daughters, Oak Ridge National Laboratory, April 12-13, 1977. Oak Ridge National Laboratory Report No. ORNL-4348. Oak Ridge, Tenn.: U.S. Department of Energy, Oak Ridge National Laboratory, 1978. 54 pp.

322 45. United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation, Report to tne General Assembly, with Annexes, pp. 200-226, 394-399. New York: United Nations, 1977. 4 6 . U . S. Environmental Protection Agency. Preliminary Findings: Radon Daughter Levels in Structures Constructed on Reclaimed Florida Phosphate Land . U . S . B~vironn~ental Protection Agency, Of f ice of Radiation Programs Report No. ORP/CSD~75-4 . Washington, D.C.: U. S. Environmental Protection Agency, 1975. 40 pp. Available f rom National Technical Information Service, Springfield, Va., as PB-257 679. 47. Wrenn, M. E., F. Steinhausler, and G. Clemente, Eds. Proceedings of the Specialist Meeting on the Assessment of Radon Daughter Exposure and Related Biological Effects, Rome, Italy, March 3-7, 1980. (in press) FORMALDEHYDE AND OTHER ORGANIC SUBSTANCES This section reviews the potential effects of formaldehyde and some other indoor organic pollutants. The sources of such pollutants are discussed in Chapter Iv. The concentrations of most of the organic . substances in question are usually unknown, because they are identified mainly as peaks on chromatograms. Their health effects must be discussed as potential, rather than known, inasmuch as the characteristics of their presence indoors have not been studied. Committees of the National Research Council have reviewed the effects of particulate polycyclic organic matters' and vapor-phase organic pollutants. s ~ Adverse health effects due to formaldehyde may occur after exposure by inhalation, ingestion, or contact. Ascribing specif ic health effects to specif ic concentrations of formaldehyde is dif f icult, because people vary in their sub jective responses and complaints. Moreover, hypersensitive persons, those with disease, and hyposensitive persons may not have been evaluated in epidemiologic studies. Thus, the threshold for response will not be co~.~-ant among all segments of the population. Interpretation of the he;. effects of formaldehyde must also consider the duration of exposure of subjects. A short-term inhalation study cannot accurately predict the effects of formaldehyde exposures of residents of conventional or mobile homes who may be exposed continuously to low concentrations. Odor irritation and tolerance may develop after several hours of exposure and modify the response to formaldehyde. EFFECTS OF FORMALDEHYDE IN ANIMALS . The reader is referred to the ARC report, or aldehlde and Other Aldehydes, 55 for detailed discussions of the effects exposure reported in experimental animal studies. formaldehyde

323 Me carcinogenic effects of formaldehyde exposure in humans have not been assessed. However, studies in rats and mice done by the Chemical Industry Institute of Toxicology have found that formaldehyde induce" nasopharyngeal carcinoma after several montbe of exposure at IS and 6 ppm for 6 in/d, 5 d/wk. Dose-related histologic changes were observed in the nasal mucosa of rats exposed at 2 and 6 ppm for the same times. Formaldehyde has mutagenic activity in a variety of microorganisms and in some insects. More work in necessary to ascertain it" mutagenic potential in germinal or somatic mammalian cell.. Such information would be used to asses" the potential hazard to persons exposed to formaldehyde. Formaldehyde ha- not been shown to be teratogenic in animals. EFFECTS OF FOI~AI~EHYDE IN HIS* The principal effect of low concentrations of formaldehyde observed in humans z~ irritation of the eyes and mucous membranes. A wide range of concentrations of airborn formaldehyde bave been reported to cause specific human health effect.. Table WI-3 shows the variability and overlap of responses among subjects. Some persons develop tolerance to olfactory, ocular, or upper respiratory tract irritation. Such factor e as smoking habits, socioeconomic status, preexisting disease, various boat factors, and interactions with other pollutants and aerosols are expected to modify tbese responses. Eve Human eyes are very sensitive to formaldehyde, responding to atmo~pberic concentrations of 0.01 ppm in some cases (when mixed with other pollutants) and producing a sensation of irritation at 0. 05-0. 5 ppm. L.acrimation i" produced at 20 pap, but damage i. prevented by closing of the eyes in response to discomfort. See Table vII-4 for summaries of effects at various concentrations. Olfactory Svetem The odor threshold of formaldehyde is usually around 1 ppm, but may be as low as 0~05 ppm in some people.5 ~ 24 26 47 75 77 '} t' Olfactory fatigue--as determined on the basis of increased olfactory thresbolds for rosemary, thymol, camphor, and tar--we" reported among plywood and particleboard workers and is presumed to be associated with formaldehyde. 9 ~ ~ ~ Olfactory fatigue can be important in the home owing to reduced sensitivity to odors a person exposed to formaldehyde might not smell other substances, such as leaking gas or burning materials. ~- *Much of this discussion is derived from tbe National Research ~uncil report, FormaldeLvde and Other Aldebydes,S. to which the reader is referred for additional details.

324 TABLES VIl-3 Reported Health Effects of Formaldehyde at Various Concentrationea Ef facts None reported Neurophysiologic ef fects Odor threshold Eye teritation Upper airway irritation Lower airway and pulmonary ef fects Pulmonary eden, inflam- ~tion, pneumonia Death averred from National Research Council.56 Approximate Foneaidehyde Concentration, ppm - 0~0~05 0.05~1.5 0.05~1.0 0.01_2.0b 0. 10-25 5-30 50~100 1004 bThe low concentration (0.01 ppm) was observed in the presence of other pollutants that may have been acting synergist ically.

325 TABLE VII~4 Eye Irritation Effects of Formaldehydea Formaldehyde Duration of Concentration, ppm Exposure Effects on Eyes Chamber single: O. 03~3.2 20~35 mini gradually Increase in blink increasing concen- rate; irri Cation t ration 13.8 30 min Irritation (and nose irritation 20 Less than ~ ~ n Discomfort and lacrimation Chamber--repeated: 0.25 5 hid for 4 d 19: -slight dis- comf art " 0.42 5 hid for 4 t 31X "slight diatoms fort" and conjune- tival irritation 0. 83-1. 6 5 hid for 4 d 94% "slight discos fort" and conjunc- tival irritation Occupational: 4-5 0.9-2.7 0. 3-2 .7 0.9-1.6 0. 13-0. 45 0.067-4.82 0.02-4.15 0.03-2.5 Indoor residential: aReprinted f rc" National Research Council. 56 (p. 7 15 ) Irritation, lacrima- tion, and discomfort in 30 min Tearing Prickling and tearing Intense irritati on and itching Stinging and burning Tearing Irritat ion Irritation

326 Respiratory Tract The nose adjusts the temperature and water-vapor content of air and removes a large proportion of foreign gases and dusts,' and the nasal mucociliary system clears foreign material deposited on it. Nasal congestion from injury may lead to partial mouth-breathings when nasal functions are impaired or the nose is otherwise bypassed for mouth-breathing, the burden of conditioning and cleaning the air falls on the oral airways and the lungs. If the nasal defense system is disturbed or if mouth-breathing occurs, greater concentrations of formaldehyde will reach the lungs, and other noxious materials ordinarily cleared from the airways may be retained. Upper Airway Irritation. Symptoms of upper airway irritation include the feeling of a dry throat, tingling sensation of the nose, and "ore throat, usually coexistent with tearing and pain in the eyes. Irritation occurs over a wide range of concentrations, usually beginning at approximately 0.1 ppm, but reported more frequently at i-11 ppmS ~ 22 . 42 h. SS '. t' thee Table ~II-3, . Tolerance to eye and upper airway irritation may occur after 1-2 h of exposures s 42 ~ S However, even if tolerance develops, the irritation symptoms can return after a 1- to 2-h interruption of exposure. 2 S ~ · ~ 2 S 3 ~ S As in the case of eye irritation, some persons seem to tolerate higher concentrations, 16-30 ppm; it is not known whether subjects develop tolerance . Lower Airway and Pulmonary Effects. Lower airway irritation that is characterized clinically by cough, chest tightness, and wheezing is reported often in people exposed to formaldehyde at 5-30 pp~e 26 2' 44 l. J. '. t06 Chest x rays of persons apparently exposed to formaldehyde at high concentrations are usually normal, except for occasional reports of accentuated bronchovascular marking-, but pulmonary-function test results may be abnormal.~°° Pulmonary edema. pneumonitis, and death result from very high formaldehyde concentrations, 50-100 ppm. ' " ~ ° ° It is not known what concentrations are lethal to humans, but concentrations exceeding 100 ppm would probably be extremely hazardous to most and might be fatal in sensitive persons. Asthma. Formaldehyde has been shown to cause bronchial asthma in h Is 3 6 Is 61 6 4 ~ 7 ~ ~ ~ ~ ~ 2 ~ ~ In some cases' asthmatic attacks are due specifically to formaldehyde sensitization or allergy; controlled inhalation studier with formaldehyde are positive in these instances.35 36 Hore commonly, formaldehyde seems to act as a direct airway irritant in persons who have bronchial asthmatic attacks from other causes. Concentrations at which attacks occur are highly variable. Bronchial asthma is characterized by hyperreactivity of airways, and the airways respond to many nonspecific inhaled irritants, including formaldehyde. The exact mechanism of the asthma syndrome related to formaldehyde exposure is not known. It has been suggested that an immunologic basis

327 is sometimes operative. However, no studies have demonstrated the presence of specific circulating immunoglobulins {IgE or IgG) in affected persons. Although formaldehyde at low concentrations may cause asthmatic symptoms in some sensitized subjects, in irritant concentrations it produces bronchoconstriction in even normal persons. Inhalation of formaldehyde fumes may cause airway hyperreactivity, an important component of bronchial asthma.~9 .. Is 75 Methacholine and histamine challenge tests have demonstrated this hyperreactivity with other environmental pollutants.~° ~i Is i7 30 S_ Skin contact with formaldehyde has been reported to cause a variety of cutaneous problems in humans, including irritation, allergic contact dermatitis, and urticaria. ~ 2 7 2 ~ ~ Allergic contact dermatitis from formaldehyde is relatively common, and formaldehyde is one of the more frequent causes of this condition both in the United States2S and in other areas. 27 The North American Contact Dermatitis Group reported that formaldehyde Is the tenth leading cause of skin reactions among dermatitis patients patch-tested for allergic contact dermatitis. Approximately 4% of 1,200 patients had positive skin reactions when tested with 2% formalin (0.8% formaldehyde) under an occlusive patch.~° Minor epidemics of allergic contact dermatitis have been described in diverse situations, for example, among nurses who handled thermometers that had been immersed in a 109e solution of formaldehyde ' and among those who were exposed to formaldehyde in hemodialysis units. " In many cases, either the initiation or the elicitation of the allergy has been caused by contact with formaldehyde or formalin, but i ~ may also result f rom formaldehyde-releasing agents used in cosmetics, medications, and germicides, from incompletely cured resins, and from the decomposition of formaldehyde-containing resins used in textiles. 49 People with cutaneous allergy deco formaldehyde have particular problems because there are so many sources of formaldehyde exposure in ordinary daily life (for example, the FDA listed 846 cosmetic formulations containing formaldehyde 2) . The skin reaction rate from cosmetic formulations containing formaldehyde has not been excessive, because it is used mainly as a preservative in shampoos, whose contact time with skin is short. Formaldehyde-releasing coarse tic preservatives, such as Quaternium-15 , have shown a greater reaction frequency than formaldehyde itself {unpublished data from Cosmetics Technology Division, Bureau of Foods, FDA). Low concentrations of formaldehyde are associated with many sources, and repeated contact with them may be sufficient to provoke responses in people with allergic contact sensitization. These sources include components of plastics, glues, antifungal disinfectants, preservatives, paper, fabrics, leather, coal and wood smoke, fixatives for histology, and photographic materials.28 Available data do not permit the determination of a degree of exposure to formaidehyde- containing products that would be safe once sensitization has occurred.

328 Most sensitized persons can tolerate topical axillary products containing formaldehyde at up to about 30 pp. witty increasing concentration, one sees a higher frequency of responders, St probably because skin penetration by formaldehyde varies from one person to another and even from one site to another on the same person. Thus, different amounts of formaldehyde may reach different target sites. The dose needed to elicit a response depends on these factors and others, such as occlusion, temperature, contact time, and vehicles Allergic contact dermatitis is ~ manifestation of cell-mediated immunity. The standard diagnostic test for this condition is the epidermal patch test. Patch testing for skin sensitization to formaldehyde resin is performed with a S-10% concentration of the resin in petrolatum. ' Although formaldehyde has been reported to cause contact urticaria, it is not yet clear whether this is immunologically mediated.52. Formaldehyde is a potent sensitizer and irritant; repeated exposure to it may also result in dermatitis. Central Nervous System Central nervous system responses to formaldehyde have been tested in a variety of ways, including by determination of optical chronexy,' electroencephalographically,2. and by the sensitivity of the dark-adapted eyes to light.S2 Responses are reported in Bone persons at O.OS ppn~ and are maximal at about 1.5 ppm. Formaldebyde at below O.OS ppm probably has little or no objective adverse effect. .' Feldman and Bonashevskaya reported that formaldehyde at 0.032 ppe produced no electroencephalographic changes and did not reach the odor threshold in five extremely sensitive subjects. 2. ~lekhins demonstrated changes in the sensitivity of the dark-adapted eye to light at about 0.08 pplD.52 imentarv Tract Ingestion of formaldehyde has been reported to cause headache, upper gastrointestinal pain,~2 2. 21 .' 5. .. allergic reactions,.. corrosive effects on gastrointestinal and respiratory tracts, 2~ 43 ·. and systemic damage.2i .' .. Accidental or suicidal poisoning with formaldehyde usually involves the ingestion of aqueous solutions, death occurs after the swallowing of as little as 30 ml of formalin. ~ 43 Gastrointestinal tract damage is most marked in the Attach and lower esophagus, with the tongue, oral cavity, and pharynx generally not severely affected. The small intestine may occasionally be involved, perforated appendix is ~ rare co~pliceeion. When the chemical inf iltrates around the epiglottis, in; ury to the larynx and trachea may occur.. ·3 ~ After ingestion, there may be lose of consciousness, vascular collapse, pneumonia, hemorrhagic nephritis, and spontaneous abortion. ~ 43 One autopsy report of a fate1 ingestion described hardening of organs adjacent to the stomach (lung, liver,

329 spleen, and pancreas), hyperemia and edema of the lungs, bilateral diffuse bronchopneumonia, fatty degeneration of the liver with subeapsular hemorrhage, renal tubular necrosis, and involvement of the brain.. .3 7° Consumer Complaints in Res idential Environments =~! ~ ~ L - ~~] ~ - A number of studies have been undertaken to determine the magnitude and extent of formaldehyde exposure of persons in the residential _,,:____, 2 ], 31 37 3. l. 85 l. Breysse reported a study of 325 persons living in 272 mobile homes, all of whom had eye and upper respiratory tract irritation. " Formaldehyde concentrations (measured in 138 instances) ranged from O to 2.5 ppms approximately 90% were less than 1 pap, and 9.4% were above 1.0 ppm.~' Of 121 persons studied, 15% had no symptoms, and approximately 34% had three or more symptom. Symptoms reported most often included eye irritation (about 30~), nose irritation (5%), respiratory tract involvement (241), headache {211), nausea (S%}, and drowsiness. In November 1977, the Connecticut Department of Health and Consumer Protection began receiving complaints from state residents who had urea-formaldehyde foam insulation installed in their home. By September 1978, 84 complaints had been received. The Department tested the 84 homes and found formaldehyde in the air in 75. The sensitivity of the testing system was reported to be less than 0.05 ppm. Health symptoms were reported by 224 residents of 74 homes, in which detectable concentrations of formaldehyde ranged between 0.5 and 10 ppm, with a mean of 1.8 ppm. The symptoms of the residents included eye, nose, and throat irritation; GI tract symptoms; headache; skin problems; and some miscellaneous complaints, such as fatigue, aches, and swollen glands. In 37%, however, symptoms occurred when formaldehyde was not detectable by the methods used. When formaldehyde was detectable (0.5-10 ppm), 49% of the occupants had eye irritation, 37% nose and throat irritation, 46% headache, and 22% GI tract syroptome; in homes with no detectable formaldehyde, 26% had eye symptoms, 41% none and throat irritation, 26t headache, and 42t GT tract symptoms. Occupational Standards for Formaldehyde It is important to consider total exposure to formaldehyde. Therefore, it should be noted that some people are exposed to it at work. The present Occupational Safety and Health Administration {OSBA) standard for formaldehyde is 3 pop, as ~ time~weighted average concentration over an 8-h workshift. In 1974, the American Conference of Governmental Industrial Bygienistn (ACGIE) recommended a limit of 2 ppm, mainly because irritation might occur above this concentration. The National Institute for Occupational Safety and Bealth (NIOSE) has recommended a workplace celling limit of 1 ppm. ~

330 Signif icance of Adverse Health Effects in Regard Population at Risk The total number of people who are exposed to for~naidehyde and who manifest adverse health effects is difficult to determine. mere is evidence that such responses may occur in a substantial proportion of the exposed population in the United States . lobe war lability in response among exposed persons makes it particularly difficult to assess the problem. Millions of persons live in mobile or conventional homes that contain either urea-formaldebyde (UF) foam insulation or particleboard made with OF resins. When measurements have been performed, a wide range of formaldehyde concentrations, from 0.01 ppm to 10.6 pop, have been reported. In most indoor environments, 24-b average formaldehyde concentration" of 0.05-0.3 ppm are not unco ~ n today. Because people may spend over 70t of their time indoors, exposure to formaldehyde from gas cooking and smoking combined with that from OF form, particleboard, and plywood could be substantial. In addition, people are exposed to formaldehyde from occupational sources, consumer products, and outdoor ambient air. Formaldehyde concentrations measured in ambient air are lower than in residences. Concentrations vary, but atmospheric concentrations are usually less than 0.1 ppm and very often less than 0.05 pro. The dose received by the 220 million people in the United States from outdoor exposure appears to be minimal, except for unusual circumstances of traffic, fuel use, or automobile density. Consumer exposures are mainly by direct contact, and contact dermatitis in an important consideration, as ban been discussed. Little is known about the magnitude of the population that is more susceptible to the effects of inhaling formaldehyde vapor. Asthmatics may constitute a segment of the general population that is more susceptible; inhalation even at low concentrations may precipitate acute symptoms. Airway hyperactivity may explain the susceptibility of asthmatics to formaldehyde at low concentrations. Using data gathered from over 1,500 metbacholine challenge tests, one can estimate the prevalence of airway byperreactivity in the population at large.' i About 9 million people in the United States bane bronchial asthma. Essentially all will react positively to ~aethacholine challenge tests and thus be considered to bave byperreactz~e airways. ~ 1 The degree of airway reactivity is variable and depends on a number of factors. It has been estimated that 30% of atopic nonasthmatic people--perhap. 10 million--have positive methacholine tests.' Townley en al. reported that 5t of nonatopic persons--anotber 8.5 million--beve positive methacholine tests.' Therefore, on the basin of calculations reported for positive methacholine challenge tests, it can be estimated that about 25 million persons in the United States, or 10-12t of the population, may be considered to have some degree of airway hyperreactivity. T'nis population could potentially be more susceptible to formaldehyde. Information on other assumed susceptible populations is limited. The U.S. Department of Health, Education, and Welfare, in a 1977 report on prevention, control, and elimination of respiratory disease,

331 estimated that 10 million persons in the United States had chronic obstructive lung disease (excluding asthma) . 87 An- unknown percentage of them will have positive methacholine challenge tests. Britt et al. ~. suggested that the presence of methacholine sensitivity and evidence of airway hyperreactivity are r isk factors for the development of chronic obstructive pulmonary disease (COPD). Perhaps patients with COPO who manifest airway hyperreactivity constitute a susceptible population, inasmuch as they react Snore acutely to airborne irritants, including formaldehyde. On the basis of sensitivity to methacholine, come atopic persons, some nona~opic subjects, and some COPD patients may constitute a potential formaldehyde-susceptible population. ThiS population could also have greater eye and upper respiratory tract sensitivity. However, many apparently normal people also react to the irritant properties of formaldehyde; this makes it more difficult to determine the susceptible population. In another attempt to estimate the susceptible population (particularly in relation to eye, nose, and throat sensitivity), information on a small number of healthy young adults exposed to formaldehyde at various concentrations for short periods was considered.S, At 1.5-3.0 ppm, more than 30% of the subjects tested reported mild to moderate eye, nose, and throat irritation symptoms, and 10-20% had strong reactions. When test subjects were exposed at O.S-1.S ppm, slight or mild eye, nose, and throat irritation was noted in more than 30%, but 10-20% still had more marked reactions. Approximately 20% of the subjects had slight ear, nose, and throat irritation in response to formaldehyde at 0.25-~.S ppm. Finally, at the lowest concentration tested, less than O.25 ppm, some exposed subj eats ~ Bless than 20 percent. ~ still reported minimal to slight eye, nose, and throat discomfort. These data might be interpreted as suggesting that there are sub jects, perhaps 10-20% of those tested. who react to formaldehyde at any given concentration. We may get further information from mobile-home surveys from which environmental and clinical data are available. Irritation symptoms were reported by 30-50% of subjects when formaldehyde concentration was g rester than 0 . 5 ppm. When the concentration was less than 0 . 5 pap, irr itation symptoms were reported in fewer than 309 of sub jects . Finally, in a more controlled study in which irritation symptoms were investigated, mild Err itation responses (doubling of blinking rate occurred in 11% of sub jects tested at 0.5 ppm. In summary, fewer than 20% but perhaps more than 109 of the general population may be susceptible to formaldehyde and may react acutely at any concentration, particularly if it is greater than I.5 ppm. People report mild ENT discomfort and other symptoms at less than 0.5 ppm, with some noting symptoms at concentrations below 0.25 ppm. Low- concentration formaldehyde exposures may produce eye, none, and throat symptoms and pass ibly lower -a i rway complaints . In some susceptible persons, an ~allergic" reaction to formaldehyde may occur at very low concentrations, causing bronchoconstriction and asthmatic symptoms. This particular type of reaction to formaldehyde appears to be uncommon; its prevalence cannot now be estimated.

332 "F=TS OF OUR ORGANIC SUBSTANCES Cardiac arrhythmia may occur through proteination of endogenous catechol~ines produced by a number of cbemicale present in the environment. various environmental chemicals have structural stmilarittes to other chemicals that may have similar effects on the ayocardium, these chemicals have a lung tissue half-life that could represent ~ long-term hazard. Examples include the polyhalogenated hydrocarbons, which may cause sudden death. The polyhalogenated hydrocarbons also bind to estrogen receptors and have been shown to have estrogenic effects in animal systems. These effects may increase HDL cholesterol and triglyceride concentrations and thus increase coronary-heart-disease incidence or mortality risk.'. Disturbances of the nervous system may occur through exposure to such chemicals as polychlorinated biphenyle (PCBe), which may be stored in fatty tissue and result in a long-ter" body burden. PC8s inhibit growth in cell cultures and interfere with the activity of a variety of enzymes.'' vapor-phase organic pollutants undergo biologic transformation sequences and metabolic reactions in the intestine, and the metabolites may be conjugated or excreted directly. Both forms may have a primary effect on the gastrointestinal tract.58 The enzymatic activity of the microflora of the gastrointestinal tract may also lead to the conversion of ingested substances, such as nitrites to nitrate-. Formation of nitrosa~ines by the reaction of secondary amines with nitrates may lead to cancer. Vapor-phase organic pollutants are enzymatically converted in the kidney and in the liver to Ire polar compounds, which are then excreted. s. These hydrocarbons may have nephrotoxic action. Solvents and chlorinated hydrocarbons may produce kidney and liver damage. ~ ' Primary skin irritants include polycyclic organic matter and other vapor-phase organic pollutants. various pathologic responses in man have been related to the use of polycyclic organic matter. Polycyclic araeatic hydrocarbons are reportedly,associated with the same kinds of work exposure. that have produced skin cancer. These materials include derivatives of fosel1 fuel, paraffin distillates, asphalt, and 1 te"~d __ - ~ _~ ~d ~ ~ 5 7 ^~t.~_~_t ~ _ ~_~__d _ __~_ _~ ~_~ _~. ~ ~ ^~ ^~ V^^D ~ ¢~ - V~ - ~~ - ~] ~~—"~= - ~~ ^~. hair follicles and sebaceous glands. 57 Vapor-phase organic pollutants (like formaldehyde) may produce a variety of akin effects. They may produce eczematous contact dermatitis and derail contact sensitivity . ~ ~ They may be absorbed percutaneously because of Volubility in the water-lipid system, they may produce skin paresthesia, 58 and they may produce eczematous reactions of an a_ute or chronic nature, including eruptions and exacerbations. 58 75 Highly water-soluble pollutants are most likely absorbed by the conjunctive locally and systemically. The vapor-phase organic pollutants, for instance, will affect the conjunctival membranes, the cornea, and the nasal mucous membranes and cause mild to acute infl~tion.S.

333 REFERENCES . .3, 1. Adams, R. Occupational Contact Dermatitis. Philadelphia: J. B. Lippincott Co., 196 9 . 2 62 pp. 2. Ad Hoc Task Force--Epidemiology Study on Formaldehyde. Epidemiolog ical Studies in the Context of Assessment of the Health Impact of Indoor Air Pollut ion. Summary and Recommendations . Bethesda, Md.: U. S. Consumer Product Safety Commission, May 10, 1979. 11 pp. Andersen, I. Formaldehyde in the indoor environment--Bealth implications and the setting of standards, pp. 65-78 ~ includes discussion) . In P. O. Fanger, and O. Valbj0trn, Eds. Indoor Climate . Effects on Human Comfort, Performance, and Health in Residential, Commercial, and Light-Industry Buildings. Proceedings of the First International Indoor Climate Symposium, Copenhagen, August 30-September 1, 1978. Copenhagen: Danish Building Research Institute, 1979. Barnes, E. C ., and H. W. Speicher . The determination of formaldehyde in air. J. Ind. Hyg. Toxicol. 24 :10-17, 1942. 5. Blejer, H. P., and B. H. Miller. Occupational Health Report of Formaldehyde Concentrations and Effects on Workers at the Bayly Manufacturing Company, Visalia. Study Report No. S-1806. Los Angeles: State of California Health and Welfare AgenQ, Department of Public Health, Bureau of Occupational Health, 1966. 6 pp- 6. Bohmer, K. Formalin poisoning. Dtsch. Z . Gesamte Gerichtl. Med. 23: 7-18, 1934. ~ in German) 7. Boucher, R. C., P. D. Pare, and J. C. Hogg. Relationship between airway hyperreactivity and hyperpermeability in Ascaris-sen~itive monkeys. J. Allergy Clin. Immunol. 64 :197-201, 1979. 8. Bouhuys, A., and K. P. van de Woestijoe. Respiratory mechanics and dust exposure In byssinosis. J. Clin. Invest. 49 :106-118, 1970. 9 . Bourne, H. G., Jr ., and S . Sefer fan. Formaldehyde in wr inkle-proof apparel produces. . . tears for milady. Ind. Med . Surg . 28: 232-233, 1959. 10. Boushey, H. A., D. W. Empey, and L. A. Laitinen. Meat wrapper's asthma: Effects of fumes of polyvinyl chloride on airways function. Physiologist 18:148, 1975. 11. Boushey, H. A., M. J. Boltzman, J. R. Sheller, and J. A. Nadel. Bronchial hyperreactivity. Am. Rev. Respir. DiS . 121: 389-413, 1980. 12. Bower, A. J. Case of poisoning by formaldehyde. J. An. Med. Assoc. 52: 1106, 1909. 13. Breysse, P. A. Formaldehyde exposure following urea-formaldehyde insulation. Environ. Health Safety News 26~1-12), 1978. 13 pp. 14. Britt, E. J., B. Cohen, H. Menkes, E. Bleecker, S. Permutt, R. Rosenthal, and P. Norman. Airways reactivity and functional deterioration in relatives of COPD patients. Chest 77(Suppl.~:260-261, 1980.

334 15. Butcher, B. T., R. M. Karr, Ce E. O'~eil, M. R. Wilson, V. Dharmarajan, J. E. Salvaggi;o, and H. Weill. Inhalation challenge and pharmacologic studies of toluene diisocyanate (TDI}-sensitisre workers. J. Allergy Clin. Imn~unol. 64 :146-152, 1979. 16 . Butcher , B. T., J. E. Salvaggio, C. E. O'~eil, H. Weill, and O. Garg. Toluene diisocyanate pulmonary disease: I'mounopharmacologic and mecholyl challenge studies. J. Allergy Clin. I~unol. 59: 223-227, 1977. 17. Butcher, B. T., J. E. Salvaggio, B. Weill, and M. M. 3iskind. Toluene diisocyanate (TDI) pulmonary disease: Immunologic and inhalation challenge studies. J. Allergy Clin. Immunol. 58: 89-100, 1976. 18. Crittenden, A. Built-in fumes plague homes. New York Times, Section 3. Business and Finance, Sunday, May 7, 1978. 19 . Curry, J . J . Comparative action of acetyl-beta-methyl choline and histamine on the respiratory tract in normals, patients with hay f ever, and sub Sects with bronchial asthma. J . Clin . Invest. 26: 430-438, 1947. 20. Earp, S. E. The physiological and toxic action" of formaldehyde. With a report of three cases of poisoning by formalin. N.Y. Med. J . 104: 391-392, 1916. 21. Ely, F. A. Formaldehyde poisoning. J. Am. Med. Assoc. 54: 1140-1141, 1910 . 22. Ettinger, I., and M. Jeremias. A study of the health hazards involved in working with flamepro-~-ed fabric. N.Y. State Dep. Labor, Div. Ind. Byg. Monthly Rev-, 34 (71: 25-27, 1955. 23 . Fassett, D. W. Aldehydes and acetals, pp. 1959-1989 . In F. A. Patty, Ed . Industr ial Hygiene and Toxicology . 2nd rev . ed . D . F . Fassett and D. D. Irish, EdS. Vol. II. Toxicology. New York: John Wiley & Sons, Inc., 1963. 24. Fel'dman, Y. G., and T. I. Bonashevskaya. On the effects of low concentrations of formaldehyde. Hyg. Sanit. 36~5) :174-180, 1971. 25. Pisher, A. A. Contact Dermatitis. 2nd ed! Philadelphia: Lea and Febiger, 1973. 448 pp. 26. Freeman, H. G., and W. C. Grendon. For~naldehyde detection and control in the wood industry. For . Prod. J. 21 (9 ): 54-57, 1971. 2 7 . Fregert, S . Manual of Contract Dermatitis . Copenhagen : ~lunksgsard, 1974. 107 pp. 28. Fregert, S., and H. J. Bandmann. Patch Testing. New York: Springer-Verlag, 1975. 78 pp. 2 9 . Gamble , J . F., A. J . McMichael, T. Willian`s , and M. Battigelli . Respiratory function and symptoms: An environmental- epidemiological study of rubber workers exposed to a phenol-for~ldehyde type res in . Am . Ind . Hyg . Assoc . J . 37: 499-513, 1976. 3 0 0 Golden, J . A ., ~ . A. Nadel, and ~ . A. Boushey . Bronchial hyperirritability ~n healthy subjects after exposure to ozone. Am. Rev. Respir . Dis. 118: 287-294, 1978. Governor 's Task Force on Insulation. Report on U-F Foam Insulation. Hartford, Ct: Connecticut Deparment of Consumer Protection, 1978. 106 pp.

335 32. Gro.an~an, L. I. Paresthesia from N2 or N2 substitute. Report of case. Oral Surg . Oral Hed. Oral Pathol. 45 :114-115, 1978. 33. Heling, B., Z. Ram, and I. Heling. The root treatment of teeth with Toxavit. Report of a case. Oral Surg. Oral Med. Oral Pathol 43: 306-309, 1977. 3 4 . Helwig, R. Wie ungef~hrlich ist Formaldehyd? DtSch. Hed. Wochenschr . 102:1612-1613, 1977 . (in German) 35. Hendrick, D. J., and D. J. Lane. Formals asthma in hospital stat f . Br . Med . J . 1: 607-608, 1975 . 3 6 . Hendr ick , D . J ., and D. J. Lane . Occupational formalin asthma. Br. J. Ind. Med. 34 :11-18, 1977. 3 7. Hilgemeier, M. W. Presentation on New Hampshire experiences with urea-formaldebyde foam, given at Ad Hoc Task Force Seminar on an Assessment of the Odor Problems from U-F Foam Insulations, Washington, D.C., December 1, 1978. 3 8 . Hogg, J. C ., P. D. Pare, and R. C . Boucher . Bronchial mucosal permeability. Fed. Proc. 38 :197-201, 1979 . 3 9. Hollowell, C. J. Presentation given at Ad Hoc Task Force Seminar on An Assessment of the Odor Problems from U-F foam Insulations. Washington, D.C., December 1 , 1978 . 40. Humpstone, O. P., and W. Lintz. A case of formalin poisoning. J. Am. Med. Assoc. 52: 380-381, 1909. 41. Jordan, W. P., Jr., W. T. Sherman, and S. E. King. Threshold responses in formaldehyde-sensitive subjects. J. Am. Acad. Dermatol. 1:44-48, 1979. 42. Rerfoot, E. J., and T. F. Mooney, Jr. Formaldehyde and paraformaldehyde study in funeral homes. Am. Ind. Hyg. Assoc. J. 36:533-537, 1975. 43. Kline, 8. S. Formaldehyd [sic] poisoning. With report of a fatal case. Arch. Intern. Med. 36:220-228, 1925. 44. Kratochvil, I. The effect of formaldehyde on the health of workers employed the production of crease resistant ready made dresses. Pr. Lek. 23:374-375, 1971. (in Czech; English abstract) Laffont, H., and J.-B. Noceto. A case of asthma due to sensitivity to formaldehyde. Algerie Med. 65:777-781, 1961. (in French) 46. Lam, S., R. Wong, and M. Yeung. Nonspecific bronchial reactivity in occupational asthma. J. Allergy Clin. Immunol. 63:28-34, 1979 4 7. Leonardos , G., D. Kendall, and N. Barnard. Odor threshold determinations of 53 odorant chemicals. J. Air Pollut. Control Assoc . 19: 91-95, 1969. 48. Lemon, L. A. A case of fatal forma' dehyde poisoning. J. Am. Med . Assoc . 42: 1492, 1904 . 4 9 . Logan, W. S. ., and H. O. Perry. Contact dermatitis to resin-containing casts . Clin. Orthop. Relat. Res. 90 :150-152, 1973. O. March, G. H. Formals poisoning; recovery. Br . Med . J . 2: 687, 1927 . 51. Marsul ~ i, F. N.., and H. I. Ma~bach. The use of graded concentrations in studying skin sensitizers: Experimental contact sensitization in man. Food Cosmet. Toxicol. 12: 219-227, 1974.

336 Helekhins, V. P. lIygienic evaluation of formaldehyde as an atmospheric air pollutant, pp. 9-18. In B. S. Levine (trans.) USSR Literature on Air Pollution and Related Occupational Diseases . Vol . 9 . A Survey. Washington ~ D.C .: U . S . Public Health Service, 1963-1964. (available from National Technical Information Service , Springf ield , Va., as T1764-11574 ~ Mills, J. CPSC warns about health hazard of foam hase material. Washington Post, Real Betate Section, Saturday, August 11, 1979. 54. Montgomery, S. Paresthesia following endodontic treatment. J. Endodon . 2: 345-347, 19?6 . 55. Morrill, E. B., Jr. Formaldehyde exposure from paper process solved by air sampling and current studies. Air Cond. Beat. Vent. 58 (7 ]: 94-95, 1961. 56. National Research Council, Committee on Aldehydes. Formaldehyde and Other Aldehydes. Washington, D.C.: National Academy Press, 1981. [354] pp. 57. National Research Council, Commit tee on Biologic Effects of Atmospheric Pollutants. Particulate Polycyclic Organic Matter. Washington, D.C.: National Academy of Sciences, 1972. 361 pp. 58. National Research Council, Committee on Medical and Biologic Ef feats of Environmental Pollutants. Vapor-Phase Organic Pollutants. volatile Hydrocarbons and Oxidation Products. Washington, D.C.: National Academy of Sciences, 1976. 411 pp. 59. National Research Council, Committee on Toxicology. Formaldehyde --An Assessment of It. Health Effects. Washington, I).C.: National Academy of Sciences, 1980. 38 pp. 60. North American Contact Dermatitis Group. Epidemiology of contact dermatitis in North America: 1972. Arch. Der~tol. 108: 537-S40, 1973. 6 1 . Nova , ~ ., and R. G. Touraine . Astute au formal. Arch . Mall Prof . 18: 293-294, 1957. (in French) 62. Odom, R. B., and B. I. Maibach. Contact urticaria: A different contact dermatitis, pp. 441-453. Chapter IS in F. N. Marzolli, and H. I. Haibach, Bds. Advances in Modern Toxicology. vol. 4. Dermatotoxicology and Pharmacology. Washington , D.C.: Hemisphere Publishing Corporation, 1977. 63. Orringer, 13. P., and W. D. Mattern. Formaldehyde-induced hemolysis during chronic hemodialysis. N. Engl. J. my. 294 :1416-1420, 1976. 6 4 . Paliard , F., L . P=cbe , C . ~cbrayet , and }3 . Sprunck . Chronic asthma due to formaldehyde. Arch. Ma1. Prof. 10: S28-530, 1949. (in Prench) 65. Parker, C. D., R. E. Bilbo, and C. E. Reed. Methacholine aerosol as test for bronchial asthma . Arch. Intern. Med. llS: 452-458, 1965. 66. Pepys, J., C. A. C. Pickering, A. B. X. Breslin, and D. J. Terry. Asthea due to inhaled chemical agents--tolylene di-isocyanate. Clin. Allergy 2:225-236, 1972. 67. Pops, V., D. Teculeacu, D. Stanescu, and H. Gavrileacu. Bronchial asthma and asthmatic bronchitis determined by simple chemicals. Dis . Chest 56: 395-404, 1969 .

337 68. Porter, J. A. E. Acute respiratory distress following formalin inhalation. Lancet 2: 603-604, 1975. 69. Proctor, D. F. The upper airways. I. ~~1 physiology and defense of the lungs. Am. Rev. Re~pir . Dis. 115: 97-129, 1977. 70 . Rathery, F., R. Piedelievre , and J . Delarue . Death by absorption of formalin. Ann. Med. Leg. Criminal. 20: 201-206, 1940. ~ in French ~ 71. Rostenberg, A., Jr., B. Bair~tow, and T. W. Luther. A study of eczematous sens itivity to formaldehyde . J . Invest . Dermatol . 19: 459-462, 1952. 72. Roth, W. G. Tylosic palmer and planter eczema caused by ste~ing clothes containing formalin. Berufsdermatosen 17: 263-268, 1969. 73. Sakula, A. E.ormalin asthma in hospital laboratory staff. L^ncet 2: 816, 1975. 74. Schoenberg, J. B., and C. A. Mitchell. Airway disease caused by phenolic (phenol-formaldehyde ~ resin exposure . Arch. Briton. Health 30: 574-577, 1975. Shipkovitz, H . D . Formaldehyde Vapor Emits ions in the Permanent-Press Fabr ice Industry . Report No. TR-52 . Cincinnati: U.S. Department of Health, Education, and Welfare, Public Health Service, Consumer Protection and Environmental Health Service, Environmental Control Administration, 1968. 18 pp. Shy, C . M., J . R. Goldsmith, J . D. Mackney, M. D. Lebowitz , and D e B. Menzel . Health Of feats of air pollution. Paper presented at meeting of American Thoracic Society, Medical Section of American Lung Association, 1978. 77. Sim, V. M., and R. E. Pattle. Effect of possible smog irri~cants on human sub Sects . J. Am. Med. Assoc . 16S :1908-1913, 1957. 7 8 . Sneddon, I . B. Dermatitis in an intermittent haemodialysis unit. Br . Med. J. 1 :183-184, 1968 . Spector , S . L., and R. S . Farr . A comparison of methacholine and histamine inhalations in asthmatics. J. Allergy Clin. Tylenol. 56: 308-316, 1975. 8 0 . Tabershaw, I . R., ~ . N. Doyle , L. Gaudette, S . B. Lame, and o. Wong. A Review of the Formaldehyde Problems in Mobile Bomes. Report to National Particleboard Association. Rock~rille, Md.: Tabershaw Occupational Medicine Associates, P.A., 1979. 19 pp. Townley, R. G ., A. R . Bewtra, N. M. Nair , F. D. Brodkey, G . D. Watt, and R. M. Burke . Methacholine inhalation challenge studies . J . Allergy Clin. Immunol. 64: 569-574, 1979 . Turiar, C. Asthma through sensitivity to formaldehyde. Soc. Franc. d 'Allergic, Seance du 18 Nov. 1952. 83. Uehara, Il. Follicular contact dermatitis due to formaldehyde. Dermatologica 156: 48-54, 1978. 84. U.S. Consumer Product Safety Commission. News from CPSC. Wednesday, August 1, 1979. 8 5. U. S. Consumer Product Safety Commission, Directorate for Hazard Identification and Analysis--Epidemiology. Summaries of in~depth investigations, newspaper clippings, consumer complaints and state reports on urea-formaldehyde foam home insulation. Washington, D.C.: U.S. Consumer Product Safety Commission. July 1978.

338 86. U.S. Department of Bealth, Education, and Welfare, National Heart, Lung, and Blood Institute. Working Group on Beart Disease Epidemiology. DREW (NTH) Publication No. 79-1667. Washington, D.C.: U.~. Department of Bealth, Education, and Welfare, 1979. 69 pp. 87. U.S. Department of Bealth, Education, and Welfare, National Heart, Lung and Blood Institute, Division of Lung Disease. Respiratory Diseases. Task Force Report on Prevention, Control, Education, pp. 84-91. DREW Publication No. {NIE) 77-1248. Washington, D.C. : U. S. Government Pr intone Office, 1977. 88. U.S. Department of Wealth, Education, and Welfare! National Institute for Occupational Safety and Bealth. Criteria for a Recommended Standard... Occupational Exposure to Formaldehyde. DHEW (NIOSH) Publication No. 77-126. Washington, D.C.: U. S. Government Printing Office, 1976. 165 pp. 8 9 . Vaughan, W. T. The Practice of Allergy , p. 677. St. Louis: The C . V. Mosby Company, 193 9 . 90. Waldbott, G. L. Health Effects of Environmental Pollutants. Saint Louis: The C. V. Mosby Company, 1973. 316 pp. 91. Walker, J. F. Formaldehyde, pp. 77-99. In A. Standen, Ed. Kirk-Othmer Encyclopedia of Chemical Technology. 2nd rev. ed. Vol. 10. New York: Interscience Publishers, 1966. 92. Wayne, L. G., R. J. Bryan, and K. Ziedman. Irritant Effects of Industrial Chemicals: Formaldehyde. DREW (NTOSH) Publication No. 77-117. Washington, D.C.: U.S. Government Printing Office, 1976. [138] pp. 93. Weger, A. Thalamischer Symptomenkomp~ex bet Formalinintoxikation. Z. Ges. Neural. Psych. 111:370-382, 1927. (in German) 94. Wisconsin Division of Health, Bureau of Prevention. Formaldehyde Case File Summary, October 23, 1978. Madison: Wisconsin Division of Health, 1978. 3 pp. 95. Wisconsin Division of Health, Bureau of Prevention. Statistics of particle board related formaldehyde cases through December 15, 1978. Madison: Wisconsin Division of Health, 1978. [4] pp. 96. Woodbury, J. W. Asthmatic syndrome following exposure to tolylene dissocyanate. Ind . Hed. Surg . 25: 540-543, 1956. 97. World Bealth Organization. Health Hazards of the Buman Environment. Geneva: World Bealth Organization, 1972. 387 pp. 98. Yef remov, G. G. State of the upper respiratory tract in formaldehyde production workers;. ah. Ushn. No,;. Gorl. Bolezn. 30 ~ 5) :11-15, 1970 . ~ in Rus~;ian; Engl ish summary) 99. Zaeva, G. N., I. P. Ulanova, and L. A. Dueva. Materials for revision of the maximal permissible concentrations of formaldehyde, in the inside atmosphere of industrial premises. Gig. Tr. Prof. Zabol. 12:16-20, 1968. (in Russian) 100. Zannini, D., and L. Russo. Long-standing lesions in the respiratory tract following acute poisoning with irritating gases. Lav. Um. 9:241-254, 1957. (in Italian; English summary)

339 FIBROUS BUILDING MATERIALS Current knowledge of the adverse health effects of fibrous building materials is reasonably complete for only one such material: asbestos. Other materials, such as f ibrous glass and rock wool, are becoming more widely used, but ~ ittle is known about their }wealth effects in human-. The continuing widespread use of f ibrous building mater ials In the absence of an adequate understanding of their potential health impacts has led to public-health concern. The details of their production, use, emission, and control are reviewed in Chapter IV. The nature of health problems varies with the organ system that may be affected. Fibrous materials can have a direct effect due to contact · . . . · . · ~ ~ _ ~ ~ It_ _ ~ ~ ~ ~ _ ~ ~ _ ~ _ ~ _ ~ ~ with the sk in, can at f ect the lungs Because or ~nna~ac~on, ana can affect the gastrointestinal tract because of inadvertent ingestion. furthermore, every organ in the body may be affected through transport of f ibers by the hematogenous or lymphatic systems. There does not appear to be any uptake of fibrous material through the skin. Inhalation is the major route of entry of f ibrous particulate matter. Deposition and retention depend on the usual factors of respiratory physiology and on fiber dimension. Most inhaled fibrous material is cleared by the mucociliary escalatory clearance mechanism, which results in inadvertent ingestion. Other inhaled particles are retained in the lung, where they accumulate. Some fibers, through uncertain routes, migrate to the pleura and stay there. Fiber translocation from the lung also occurs via the hematogenous and lymphatic systems, with eventual accumulation of fibers in virtually every organ of the body e The fractions that are disseminated by this mechanism and through the gastrointestinal system are not known. That dispersion tales place through the gastrointestinal tract has been clearly shown in animals. ~ Garage of asbestos or the presence of asbestos in drinking water or food result" in transport across the intestinal wall into the per itoneal cavity and into the blood~trea~n, which leads to deposition throughout the body. After garage, asbestos has been found in all organs examined, including kidney, liver, pancreas, and brain. It can also cross The placenta. ~ Asbestos and other fibrous materials are not metabolized after enter ing the body , but there is leaching of chemical constituents, which varies with fiber type and size. Fibers can take up biO\ - iC residence in many organs, and most fibers remain uncoated. Some fibers become coated with an iron-protein matrix and form an Asbestos body. when asbestos is the core material. When the core in not identified, it is known as a ~ferr~ginous body. n The intracellular process that produces thin coating has been well documented by Suzuki and Churg.~' Some structural and compositional changes occur after f ibex are taken up in tissue, particularly In one lung . In ache case of chrysotile, magnesium leaches out of the fiber; this ultimately changes the structure of chrysotile and makes quantitative recovery from lung tissue less secure over time. The mechanism by which asbestos and other fibrous materials produce fibrosis appears to be different from that of ~ ilica, which acts by causing secondary lysosoma3. release of enzymes in macrophages that lead to a fibrotic tissue reaction. me

340 interaction of asbestos and ~crophages in Vito ts less well understood, but some intact ~crophages contain small fiber-, and others surround parts of large fibersO SPECIFIC H~= EFFECTS Health effects resulting from exposure to fibrous materials can be divided into nonmalignant and malignant effects. A division into acute and chronic effects is of little value. Except for the acute cutaneous irritation produced by fibrous gl888 products, including t - se treated with resins and lubricants, the important effects of exposure to fibrous ~teriale are chronic, and they often have very long latent periods. No initial short-tersl health effects of any major consequence are seen in either healthy adults or persons with preexisting conditions, because of the long latent period of the effects. All mineral fiber types have been abown in laboratory animals to be capable of producing a wide spectrum of disease when administered as long, thin f ibers . Nonmalignant Effects Cutaneous Effects. Asbestos has been shown to produce granulomatoun warts on the hands, and asbestos fibers have been found in these growths. Whether asbestos alone ts the causative agent or viruses play a role teas not been studied. It has been known for several decades that fibrous glass materials can produce severe irritation in those working with them. This may be a function of direct physical contact or of ~ chemical process related to resins and lubricants. It can be prevented by the wearing of long-~leeved clothing and gloves. Findings in Sputum. Asbestos bodies were first described (although not so named until 1929) on the basis of autopsy findings in two deaths in 1906. 26 These fibers costed with iron-protein have been used as a marker for previous asbestos exposure, not as an indicator of disease or severity of disease. As a marker of exposure, their appearance works well. The coating of fibers in vitro varies with species. Both uncoated f ibers and asbestos bodies have been found in sputum and glare Bone guidance as to extent of exposure, particularly if "e exposure has been intense. Digestion and examination of lung tissue often reveal the presence of asbestos bodies and fiberes in approximately half of 3,000 consecutive autopsies in New York City, optical microscopy uncovered asbestos bodies in lung tissue.2. Electron microsc:opic examination is preferred for more complete evaluation. Pulmonary Disease. The most important nonmalignant health effect of asbestos exposure is the change in the pulmonary sys tea. Asbestosis, lung scarring, can result from asbestos exposure and is a

341 leading cause of death among some occupationally exposed groups. ~Asbestosis. refers to the fibrotic process of either the lung parenchyma or the visceral pleura. If one is referring only to lung t issue, the term ~parenchyma1 asbestosis. is preferable. ~Asbestosis. is a clinical diagnosis that can be made in the absence of active symptoms or any apparent ill health . ~ Impairment. is a clinical j udgment based on f indings in the history and in pays ical and laboratory examinations. Not everyone with disease is impaired. The presence of disease without impairment should always suggest the possibility of future impairment or future additional disease. ~Disability. is a legal concept related to the absence or presence of disease and impairment, often with regard to specific functions. Fibrosis of the lung parenchyme after asbestos exposure is related to the degree of exposure and the period since the beginning of exposure. It has been documented ~ ° that increasing exposure leads to an increase in the incidence of asbestosis and an increase in its severity. The degree of asbestosis is usually measured in terms of the ILmU/C classification for x-ray films (issued by the International Labour Office, 1971, Geneva), which evaluate-. changes on a 12-point scale and includes types of changes and associated f indings. Radiologically evident asbestosis generally develops only after considerable time has passed since f irst exposure, unless exposure has been intense. The appearance of extensive asbestosis in less than 20 yr is unusual. If asbestosis does occur within that period, it will probably not be far advanced. The exposure need not be continuous over this period; and relatively brief exposure may be sufficient to cause disease many years later. In addition to parenchymal asbestosis, changes may develop in the pleura . Pleural f ibrosis, with or without calcif ication, is a colon f inding after asbestos exposure. There is increasing evidence that the extent of exposure required to produce pleural changes may be less than that associated with parenchymal changes.2' There is no reliable correlation between a finding of nonmalignant pulmonary changes and the predictability of development of neoplasia, which can develop without radiologic evidence of asbesto~is . Hal ianant Ef feats A var. iety of malignant neopla~ms are associated with exposure to asbestos . Lung Cancer. Lung cancer is found in great excess among workers occupationally exposed to asbestos. This has been noted with all commercially important types of asbestos. Asbestos-related tumors tend to be in the lower lobes and per ipheral, following the pattern of the parenchymal changes of asbes~cosis, although neoplasms are also increased in the upper lobes. The cell type distribution does not appear to be altered with asbe~tos-related cancers. 2 2 Cigarette- smoking acts synergistically to increase the risk of developing lung cancer. ~ ~

342 Mesothelioma. Both pleural and peritoneal mesotheliomas are seen after exposure to asbestos. Pleural me8Othelioma8 are generally more common; peritoneal me8Otheliamas tend to take longer to develop and tend to occur in large numbers only among more heavily exposed population.. Their incidence is not related to cigarette-smoking. Other Cancere. Other malignancies are found in excess after . asbestos exposure. Of particular importance is the increase in gastrointestinal tract cancers, particularly of the colon and rectum, stomach, and esophagus.42 Pancreatic cancer does not appear to be increased. Oropharyngeal cancers and laryngeal cancers are also increased.. 2 Among women, ovarian cancer has been reported after asbestos exposure,). but more data on this question are needed. LABORATORY EVIDENCE OF HEALTH EFFECTS An increasing number of reports have demonstrated adverse effects in vivo or in vitro, many in parallel with demonstrated human health _ _ _ effects. In Vivo Ef feats _ vivo experimentation has documented all the major health effects caused by asbestos, and in some cases other materials have caused imilar changes . Inhalation. Inhala~cion studies with asbestos of several fiber types have documented the risk in animals of developing asbestosis and malignancy, including lung cancer and mesothelioma. Wagner et al.ss And nAVi. - ~ al lo hay. shown that all mailer fiber tvDes produce both malignancies noted, and that the usual do~e-respon$e relationship holds. Warner et al. and Bernstein et al.. are conducting studies to evaluate the hazards associated with inhalation of fibrous glass products and talc. Inj ection . Intratracheal, intrapleural, and intraper itoneal injection. into laboratory animals of asbestos, f ibrous glass, and other fibrous material have been associated with disease production. Lung cancer has been produced in hamsters with intratracheal instillation. Peritoneal mesothelioma has been produced by injections or other placement of asbestos into the pleural cavity. Stanton et al. ., ·. produced neoplasms with long, thin fibers of var ions k inds, including asbestos, f ibrous glass products, and such other fibrous materials as fibrous dawsonite, an aluminum carbonate. Peritoneal mesotheliomas have developed after intraPeritoneal injections of asbestos.~. Wright and Kuschner-- tnsez~ea asbestos, glass, and other fibers into guinea pigs intratracheally; when the f ibers were long and thin, all the materials produced lung f ibrosis. , , ~ .

343 In Vitro Effects _ vitro techniques are increasingly being used to study the effects of asbestos and other fibrous materials. A comprehensive review on this subject was published by Barington et al.' Macrophages. Asbestos and other fibrous materials may be toxic to macrophages. This was first shown by Harington et a1.~, in preparations of freshly prepared macrophages and more recently by Wade et al. 52 in continuously cultured malignant macrophage-like cells. Thus' the cytotox~c potential or a variety of fibers is clear. There is new evidence that the cytotoxic potential of fibrous materials may parallel their carcinogenic potential.. 53 Miller has reviewed the effects of asbestos on macrophages as shown with electron mICrOscopy. 3 0 Fibroblasts. Addition of asbestos to culture. of fibroblasts has demonstrated alterations in both cellular ozocnem~stry and morphologic appearance.3' so These chemical alterations have not yet been related to changes in human lung tissue. Other Cell Systems. Other cell systems have been used to study the effects of asbestos. Schnitzer et al.3' used erythrocytes as a test system for the evaluation of biologic effects of a variety of dusts, and work with mesothelial cell cultured has begun to increase the understanding of changes in this cell type brought about by exposure to such dusts as asbestos. Organ Culture Another approach to the understanding of the ef facts of asbestos and other dusts has been the use of organ culture systems. - Reman et al. '~ investigated the effects of crocidolite on hamster tracheal cultures, and Frank ~ 2 studied the effects of amosite and chrysotile. Hyperplasia of basal cells was the most prominent morphologic change noted. Rajan _ al. 35 studied the effects of asbestos on Suntan pleura in organ culture and also noted byperplasia after the addition of asbestos. Fibrous glass products are currently under study with organ culture techniques. EPIDEMIOLOGY AND OCCUPATIO=L E=OSU" The f irst case of asbestosis reviewed for compensation purposes was observed in 1906 in England by Murray.32 Additional cases were reported later, and the disease was better understood by 1930. In 193S, Lynch and Smith27 reported the first case of lung cancer in a man who worked in an asbestos factory and suggested a causal relationship. The historical development of the understanding of asbe~tos-related disease was reviewed by Selikoff and Lee. ~ 3

344 Asbestosis Canes of asbestosis were known earlier, but it was during 1930 that Merewether and Pricer' extensively reviewed the association of asbestos exposure and the development of fibrosis. More than 251 of 363 asbestos manufacturing workers had evidence of pulmonary fibrosis related to their exposure to asbestos. Similar findings were reported in the United States by tanza et al.25 For the development of asbestosis in relation to exposure and to the period from onset of exposure, the information reported by Selikoff and Lee.' clearly demonstrated a dose-response relationship and showed that development and severity of asbestosis increase with the. Other Chronic Lung Diseases There hare been few epidemiologic reports of other chronic lung disease after exposure to nonasbestos fibrous materials. Bayliss et al. ' reported no increased lung-cancer mortality, but an increase in nonmalignant respiratory-disease deaths among fibrous~glass production worker.. Boehlecke et al. 5 have reported on a group of workers exposed to wollastonite, a fibrous monocalci~ silicate used as an asbestos substitute. may observed none of the clinical stigmata usually seen with asbestos exposure. Only 36% of workers had been exposed more than 15 yr before the study. Cancer Epidemiology The 195S report by Dollar was a landmark in the establishment of a relationship between lung cancer and asbestos exposure. Other reports soon followed; several were represented at the New York Academy of Sciences in 1965. 57 Before 1960, n~esothelionu had been a rarely reported disease, although some cases had been seen in asbestos workers. In that year, Wagner _ al.56 reported 47 cases that had occurred during a 4-yr period in the ast~estos-mining area of South Africa. Further reports appeared soon after, and the strong causal relationship with aBbe8to8 exposure has now been filmy established. Cochrane and Webster' found that 69 of 10 cases of mesothelioma at one South African hospital were associated with subetantis1 asbestos exposure. Principles Through the epidemiologic investigations of occupationally exposed groups, several principles of exposure~disease relationship have become clear. The question of latency is now well understood: in general, 15-20 yr must pass before the signs of marked asbestos-related disease are detected, by either x-ray study, pulmonary-function results, or physical findings. me exposure may have been brief; if it was intense

345 enough, disease may result, although in almost all canes there is a long latency period. It has become clear that both the severity of asbestosis and the risk of developing lung cancer or mesothelioma depends on the total exposure to f ibers. Because of the paucity of data on workplace or environmental concentrations, exposures are almost never known exactly, and only rough estimates of exposure can be agreed on by most author it ies . Exposure in the workplace can be either direct or indirect. In many cases, indirect, or ~bystander, ~ exposure has proved hazardous . This has been established in shipyard workers' ~' and maintenance workers.26 Thus, indirect exposure can be hazardous to people who work near those specif ically assigned to handle asbestos . Other Fibrous Mineral Mater ials and Dusts No epidemiologic investigation has demonstrated substantial health hazards related to other fibrous materials and dusts that might contaminate the indoor environment. The asbestos substitutes used In construction are relatively new, at least with respect to their possibly producing human health effect=, and little is known of their hazards . Those materials include the slag wools, rock wools, glass wools, and f filaments. The subject of man-made mineral f ibers has been reviewed by Hill20 and Wagner et al.S. NONOCCUPATION" EXPOSURE Much less Is known about exposure to fibrous materials away from the workplace than about occupational exposure. Ne ighborhood Exposure There have been several studies of exposures of persons living near asbestos production facilities . Wagner 's original report on cases of mesothelioma in South Africa included mainly persons who lived near asbestos mines or along the routes of transport. Newhouse and Thompson ~ 3 showed that a substantial number of cases of mesothelioma at the London Hospital between 1910 and 1965 were in persons who lived within 0.5 mile of a production facility in East London. A more recent study showed no such relationship in persons who lived near an asbestos production facility in New Jersey, at least in less than 35 yr from onset of i ts operations . ~ ~ Of increasing recent interest is the situation in parts of Turkey, where it appears that naturally occurring fibrous zeolites in the environment give rise to numerous cases of mesothelioma among the general population. 2

346 Family Exposure Among the best recorded relationships between household contamination and disease development are those ~ng families of asbestos workers. Particularly striking is the development of mesotheliomas hong wives, children, and other family contacts of asbestos workers who beve brought asbestos home on their persons and clothing. Contamination of the living environment resulted t 20 yr or more later, mesotbeliomas appeared. In addition, roughly one-third of such persons had x-ray changes consistent with asbestos)-. Studies on this subject were recently reported by Anderson et al. 1 and Tag non et al. so Exposure in Buildings Only within the last several years teas the scientific community become aware of the widespread use of asbestos in public buildings in ways that might be related to substantial risk. Asbestos is used in insulation and fireproofing materials, in ornamental decoration and soundproofing, and in large guantities on surfaces in public areas. Its use in school buildings has been the subject of recent reviews'. " that included discussion of potential health problems and suggestions of control measures. Public areas in other building. can also become contaminated, especially during routine or other maintenance procedures, which may aerosolize friable asbestos coatings. There have been few measurements of air concentration. Especially lacking are studies that put members of the general population or "ct~oolabildren under prospective surveillance to see what ~ if any) adverse health effects occur. Refinement of risk estimates of effects in the general population awaits additional understanding and measurement of the potential effects of long-term low~concentration exposure. The relationship of total exposure to the age when first exposure occurs is not known. Other Exposures The general water pollution special concern _ . . . . ~ environment may became contaminated f ram with asbestos or other fibrous material. for houses in communities with mining and processing ambient sir or This is of facilities. Bousehold exposures can also occur elsewhere, although few measurements bare been made to demonstrate the extent of such exposures. In Montgomery County, Maryland, widespread ambient-air contamination has resulted from the long use of crushed rock containing asbestos for the paving of roads, parking lots, and playgrounds. Air concentrations in tbe community were reported to be similar to those in some working environments,' and the particular asbestos that was contaminating the air was shown to have substantial biologic activity ~ ~

347 Water contamination can also occur from the dumping of industrial wastes into lakes, as evidenced by the asbestos found in the water of Borne communities that Cake their municipal supplies from Lake Superior. 2 3 Consumer products brought into the home may contain asbestos. The Consumer Product Safety Commission has banned artificial fireplace logs and bair~dryer. containing asbestos. The subject of consumer-product asbestos hazards has been discussed by Franklin. i. It is clear that the hou~ebold can become contaminated. Although scientific knowledge of specific healLb effects is sparse, the state of knowledge about the adverse consequences of asbestos exposure elsewhere justifies a cautious approach to any exposure. REFERENCES 7. 9. 1. Anderson, H. A., R. Lilis, S. M. Daum, and I. J. Selikoff. Asbestosi" among household contacts of asbestos factory workers. Ann. N.Y. Acad. Sci. 330: 387-399, 1979. 2. Bared, Y. I., M. Artv~nl~, and A. A. Cabin. Environmental mesothelioma in Turkey. Ann. N. Y. Acad. Sci. 330: 423-432, 1979. 3 . Elaylis" , ~ . L., J. M. Dement , J. R. Wagoner , and B. P. Blejer . Mortality patterns among fibrous glass production workers. Ann. N.Y. Acad. Sci . 271: 324-335, 1976. 4. Bernstein, D. M., R. T. Drew, and M. Kuschner. Experimental approached for exposure to sized glass f ibers. Environ. Bealth Perepect. 34:47-57, 1980. (includes commented Boehlecke , B . A., D. M. Shabby, M. R. Petersen , T. R. Bodous , and J. A. Merchant. Respiratory morbidity of wollastonite workers. Am. Rev. Respir. Dis. 117 (Suppl.} :219, 1978. (abetract) Chamberlain , M., R. C. Brown , R. Davies , and D. M. Gr if f it's . In vitro prediction of the patbogenicity of mineral dusts. Br. J. Exp. . Pathol. 60: 320-327, 1979. Cochrane, J. C., and I. Webster. Mesothelioma in rela~cion to asbestos f ibre exposure . S . Af r . Med . J. 54: 279-281, 1978 . 8. Cunningham, H. M., and R. D. Pontefract. Asbestos f ibers in beverages, drinking water, and tissues: Their passage through the intestinal wall and movement through the body. a. Assoc. Off. Anal. Chem. 56: 976-981, 1973. Cunningham, B. M., and R. I). Pontefract. Placental transfer of asbestos. Nature 249 :177-178, 1974. 10. Davis, J. M. G., S. T. Beckett, R. E. Bolton, P. Callings, and A. P. Middleton. Mans and number of fibres in the patbogenesis of asbesto"-related lung disease in rata. Be. J. Cancer 37: 673-688, 1978. ' 1. Doll, R. Mortality from lung cancer in asbestos workers. Br. J. Ind . Med ~ 12: 81-86, 1955. 12. Frank, A. L. Asbestos-induced changes in hamster trachea organ culture . In R. C. Brown, M. Chamberlain, R. Davies, and I . P. Gormley, Ede. The In vitro Effects of Mineral Dusts. London: Academic Press Inc., London Ltd., 1980.

348 15. 17. 13. Frank, A. L., A. 11. Rohl, M. J. wade, and L. E. LlFkln. 8tological activity In vitro of chrysotile Spared to it8 quarried "rent rock (platy serpentine). J. B`vlron. Pathol. Toxicol. 2s1041-1046, 1979 . 14. Franklin, B. 8. Public health control of en~rlron~ntal asbestos dleease: Consumer products. Ann. N.Y. Aced. Sci. 330 sd97-501, 1979. Graham, J., and R. Graham. ovarian cancer and asbestos. Environ. Res . 1 s 115-128, 1967 . 16. Remand, E. C., L. Garflnkel, I. J. Sellkoff, and W. J. Nlcholson. lSortallty experience of realdents In the neighborhood of an asbestos factory. Ann. H.Y. Aced. Sc1. 330: 417-422, 1979 . "rlngton, J. S., A. C. Allen, and D. V. 8adam1. Mineral flbere: Chemical, physiochemical, and blologlcal properties. Adv. Pharmacol . Che~ther . 12: 291-402, 1975 . Marries, P. G. Asbestos hazards In Nave1 Dockyards. Ann. Occup. Bye . 11: 135-145, 1968 . 19. Marries, P. G. Experience with SIB—808 disease and its control in Great Britaints Naval Dc~ckyerde. En~lron. Res. 11:261-267, 1976. 20. Hill, J. W. Health aspects of man-made mineral fibres. A review. Ann . Occup. Byg . 20 :161-173, 1977 . 21. Jaurand, M.~C., B. Replan, J. Thiollet, M.~C. Pinabon, J.-F. 8ernaudin, and J. Bignon. Phagocytosts of chrysotile fibers by pleural aesothelia1 cells in culture. Am. J. Patbol. 94s529-538, 1979. 22. Kennerstein, H., and J. Churg. Pathology of carcinoma of the lung associated with asbestos exposure. Cancer 30sI4-21, 1972. 23. Lander, A. M., C. M. ~ggiore, W. J. Nicholson, A. H. Rohl, I. B. Rubin, and I. J. Selikoff. me contamination of Lake Superior with amphibole gangue minerals. Ann. N.Y. ACad. Sci. 330: Sd9-512, 1979. 24. Longer, A. M., I. J. Selikoff, and A. Sastre. Chrysotile asbestos in the lunge of persons in stew York City. arch. Textron. Bealth 22: 348-361, 1971. "nzs, A. ~ ., W. A. McConnell , and J. W. Fehne} . Effects of the inhalation of asbestos dust on the lunge of asbestos workers. Public Bealth Rep. SOs1-12, 193S. Lilts , R., S . Am, ~ . Anderson , H. Sirota , G. Andrewe , and I . J . Selikoff. Asbestos disease in maintenance workers of the chemical industry. Ann. H.Y. Acad. Sc1. 339 :127-135, 1979 . . Lynab, R. M., and W. A. Seith. Pu~nery asbestoste. ITI. Carcinoma of lung in asbesto~licosis. Am. J. Cancer 24:56-64, 193S. 28. forehand, F. Dber Eigentumliche Pigamnthris~lle in den Lungen. otech . Path. Ges . Verh . 17: 223, 1906. 29. Herewether, E. R. A., and C. w. Price. Report on Effects on Asbestos Dust on the Lungs and Dust Suppression in the Asbestos Industry. London: Elis ~jesty's Stationery Office, 1930. 34 pp. 30. Miller, R. me effects of asbestos on ~crophages. CR`: Crit. Pan. Toxicol. 5: 319-354, 1978. 31. glossy, B. T., J. B. Kessler, B. W. hey, and J. 13. Craighead. Interaction of crocidolite asbestos with hater respiratory aucose in organ culture. Lab. Invest. 36sI31-139, 1977.

349 45 Murray, H. M. Report of the Departmental Committee on Compensation for Industrial Disease. London: His Majesty's Stationery Office, 1907. 3 3 . Newhou~e , M. L., and H . Thompson . Hesotheliama of pleura and peritoneum following exposure to asbestos in the london area. Br. J . Ind. Med . 22: 261-269, 1965. 3 4 . Nicholson , W . J ., A. N . Rohl , R. N. Sawyer , E . J . Swoszowski , Jr ., and J. D. Todaro. Con~crol of sprayed asbestos surfaces in school buildings: A feasibility study. Report to the National Institute of Environmental Health Sciences. New York: City University of New York, Mount Sinai School of Medicine, Environmental Sciences Laboratory, 1978 . [1211 pp. 35. Rajan, K. T., J. C. Wagner, and P. H. Evans. The response of human pleura in organ culture to asbestos. Nature 238:346-347, 1972. 36. Richards, R. J., and F. Jacoby. Light microscope studies on the effects of chrysotile asbestos and fiber glass on the morphology and reticulin formation of cultured lung fibroblasts. Environ. Res. 11:112-121, 1976. 37. Rohl, Acts., A. M. Langer, and I. J. Selikoff. Environmental asbestos pollution related to use of quarried serpentine rock. Science. 196:1319-1322, 1977. 38. Sawyer, R. N., and E. J. Swoszowski, Jr. Asbestos abatement in schools: Observations and experiences. Ann. N.Y. Acad. Sci. 330:765-775, 1919. 39. Schnitzer, R. J., G. Bunescu, and V. Baden. Interactions of mineral fiber Surfaces with cells in vitro. Ann. N.Y. Acad. Sci. 172: 7S9-772, 1911. 40. Seidman, H., I. J. Selikoff, and E. C. Hammond. Short-term asbestos work exposure and long-term observation. Ann. N.Y. Acad. Sci. 330:61-89,'1979. Selikoff, I. J., E. C. Hammond, and J. Churg. Asbestos exposure, smoking, and neoplasia . J . Am. Med. Assoc . 204 :106-112, 1968 . Selikoff, I. Je' E. C. Hammond, and H. Seidman. Mortality experience of insulation workers in the United States and Canada, 1943-1976. Ann. N.Y. Acad. Sci. 330 :91-116, 1979. Selikoff, I. J., and D. H. K. Lee. Asbestos and Disease. New York: Academic Press Inc., 1978. 549 pp. 44 . Shin , M. L., and H. I . Firminger . Acute and chronic effects of intraper itoneal inj ection of two type" of asbestos in rats with a study of the histopathogenesis and ultrastructure of resulting mesotheliomas . Am. J . Pathol . 70: 291-313, 1973 . Silverer, R. Z. Asbestos in school buildings: Results of a Nat ion~wide survey. Ann. N.Y. Acad . Sci . 330: 777-786, 1979. 46 . Smith, W. E., L. Miller, R. E. Elder, and D. D. Hubert . Tests for carcinogenicity of asbestos. Ann. N.Y. Acad. Sci. 132:456-488, 1965 . 47. Stanton, M. F., M. Layard, A. Tegeris, E. Miller, M. May, and E. Kent. Carcinogenicity of fibrous glass: Pleural response in the rat in relation to fiber dimension. J. Nat. Cancer Inst. 58:587-603, 1977.

350 S5. 480 Stanton, M., and C. Wrench. Mechanisms of mesothelioma induction with asbestos and fibrous glass. J. Nat. Cancer Tnst. 48:797-821, 1972. 49. Suzuki, Y., and J. Churg. Structure and development of the asbestos body. Am. J. Pathol. 55:79-107, 1969. 50. Tagnon1 I. J W. J. Blot, R. B. Stroube' N. E. Day, L. E. Morris, D. B. Peace, and J. F. Fraumeni, Jr. Mesotheli~na associated with the shipbuilding industry in coastal Virginia. J. Cancer Bee. 40: 3875-3879. 1980. S1. Wade, M. J., L. E. Lipkin, and A. I,. Frank. Studies of in vitro asbestos-cell interaction. J. Environ O Pathol. Toxicol. 2: 1029-1039, 1979. . Wade, M. J., L. E. Lipkin, R. W. Tucker, and A. L. Frank. Asbestos Qtotoxicity in a long term macrophage-like cell culture. Nature 264: 444-446, 1976. 53. Wade, M. J., L. E. Lipkin, M. F. Stanton, and A. L. Frank. P388D~ in vitro Qtotoxicity assay as applied to asbestos and other minerals: Its possible relevance to carcinogenicity. In R.C. Brown, M. Chamberlain, R. Davies, and I. P. Gormley, Eds. The In Vitro Effects of Mineral Dusts. London: Academic Press Inc., London Ltd., 1980. 54. Wagner, J. C., G. Berry, and F. D. Pooley. Carcinogenesis and mineral fibres. Br. Med. Bull. 36: S3-56, 1980. Wagner, J. C., G. Berry, J. W. Skidmore, and V. Timbrel1. The effects of the inhalation of asbestos in rats. Br. Je Cancer 29: 2S2-269, 1974. 56. Wagner, J. C., C. A. Sleggs, and P. Marchand. Diffuse pleural n~esothelians and asbestos exposure in the North Western Cape Province. Br . J. Ind. Med. 17: 260-271, 1960. 57. Whipple, I1. E., and P. E. Ran Reyen, Eds. Biological Effects of Asbestos. Ann. N.Y. Acad. Sci. 132 :1-766, 1965. 58. Wright, G. W., and M. Ruschner. The influence of varying lengths of glass and asbestos fibres on tissue response in guinea pigs, pp. 455-472. In W. B. Walton Inhaled Particles Ill. Proceedings of an International Symposium Organized by the British Occupational Hygiene Society, Edinburgh, 22-26 September 1975. Part 2. Oxford: Pergaruon Press, 1977. COMBUSTION PRODUCTS Miss section concerns the effects of the exposure of people in .- ~ buildings to the products of fossil-fuel Combustion that takes place in those buildings. Such fuels are consumed in space- and water-heating, clothes~drying, cooking, and operating ga~-powered refrigerators and propane torches. When Invented flames are used in maintenance, modification, and repairs or in hobby activities. some of the effluents are similar to those of flames used for cooking and space-heating-- carbon monoxide and nitrogen dioxide. As discussed in Chapter TV, additional toxica~-s may also be released, depend ng on the composition of the objects he red and the temperatures attained.

351 The present discussion is limited to the effects of the products of fossil-fuel combusion. It excludes, for example, the materials vaporized by the application of a flame to a cooking pot, frying pan, or metal object involved in maintenance or hobby activities. With respect to cooking, this exclusion can be justified on the basis that gas range and an electric range do not differ substantially in the composition and magnitude of pollutants released during cooking. The Contribution of the cooking processes themselves to overall indoor pollution may be important, especially with respect to odor characteristics and the concentrations of suspended particles. But the effluents of cooking processes are highly variable, and their effects, if any, on the health of residents are generally not known. Cigarette combustion is also excluded, in that it is discussed in the next section of this chapter. For the products of indoor combustion to constitute a health stre~sor, they must be able to cause toxic effect" and they must be present in occupied Spaces at sufficient concentrations and for sufficient durations to manifest their toxicity in a substantial part of the exposed population. The extent to which products of combustion contaminate indoor air depends on the composition of the fuel, the temperature of combustion, the efficiency of combustion, the efficiency of the renting of the combustion products to the outdoor air, and the isolation of discharged air from makeup air that enters the occupied space. The most important factor is usually the presence or absence of effective venting of the combustion products to the outdoor air. If the venting is effective, there should be relatively little buildup of combustion effluents indoors, even when liquid fuels (such as kerosene) or solid fuels (such as wood, charcoal, coke, and anthracite) are burned. However, the use of liquid and solid fuels makes it more difficult to achieve effective venting. When venting of combustion effluents is incomplete, even the burning of the cleanest of fuels (natural gas ~ may liberate excessive amounts of toxic gaseous effluents, specifically carbon monoxide and . nitrogen dioxide. There may also be measurable amounts of nitric oxide, unburned fuel (methane, ethane, propane, etc. ), products of pyrosynthesis (e.~., aldehydes), and carbonaceous particles. The products of indoor combustion that are most often of health concern are carbon monoxide and nitrogen dioxide. Airborne concentrations of these pollutants have been measured in a n''mher of epidemiologic studies; but other air pollutants were also present, ano their concentrations were usally not measured. At best, epidemiology can demonstrate an association, but it cannot establish causality. _ CARBON MONOXIDE Exposure to carbon monoxide (a product of incomplete combustion of any fossil fuel) constitutes a long-establi~hed and well known acute hazard. Exposure at over 500 ppm for more than ~ h can lead to approximately 20% of carboxyhemoglobin saturation. Exposure at 1,500 pop for 1 h is dangerous to life. Such high concentrations can

3S2 result from improper ca~bustion--e.g., without an adequate supply of combustion air. The issue of a threshold for adverse carbon monoxide effects was addressed in a 1977 National Research Council report: ·2 Whether there ts ~ threshold carboxyhemoglobin concentration for an adverse effect is still unknown.... The mechanism for adverse carbon monoxide effects is a fall in capillary oxygen partis1 pressure (PO2) due to carbon monoxide binding to hemoglobin, and therefore a pertinent question is whether any fall in capillary pO, no matter ha' 8~1, results in an adverse effect on tissues. he ts know that many tissues, in order to keep intracellular pot nearly constant, can adapt to acute falls in arterial PO2 with resulting falls in capillary PO2. we major adaptation mechanism in many tissues is probably recruitment of capillaries to give a decrease in oxygen diffusion distance between capillary blood and mito`:hondria. If such a mechanism occurs as carboxyhe~oglobin increases, it is unlikely that adverse carbon monoxide effects occur at carbo~hemoglobin concentrations near zero and more probable that ~ threshold exists at a carboxyhemoglobin Concentration where adaptation cannot compensate. . . . The tissues Cost sensitive to the adverse effect of carbon monoxide appear to be heart, brain, and exercising skeletal muscle. Evidence has been obtained that carboxyhemoglobin concentrations in the 3-5% saturation range may adversely affect the ability to detect sas11 unpredictable environmental changes (vigilance). mere is evidence that acute increase- of carboxybemoglobin to above 4-51 in patients with cardiovascular disease can exacerbate their symptom when the carboxyhemoglobin is as low as 51.... In the studies of the effect of carbon monoxide on vigilance and cardiovascular symptoms, there was no attest either to determine the effect of lower carboxyhe~oglobin concentrations or to look for ~ threshold. When aerobic metabolism of exercising skeletal muscle was studied, an apparent threshold was found. At a carboxybemoglobin concentration below 5t, a measurable effect on oxygen uptake could not be demonstrated. ~ * ~ me current SPA standard for carbon monoxide is 9-ppm maximum for 8-fur average exposure, or 35-ppm me: cimum for 1-fur average exposure e Approximate calculated carbon monoxide uptakes for varying levels of activity after exposure to these concentrations are given below. Exposure Resting Moderate Activity Beaw ACtiVity 9 ppm, 8 he 1. 3% sat 1.4% sat 35 ppe, 1 he 1.3% 2.2% 1.4% sat 2.9%

353 . . . The current EPA standard is mainly justified on the basis of adverse carbon monoxide effects in patients with cardiac and peripheral vascular disease and effects of carbon monoxide on oxygenation of skeletal muscles in exercising normal human subjects. There appears to be an adequate safety f actor between the lowest carboxyhe~lobin concentration that has been demonstrated to cause adverse effects and the maximal carboxyhemoglobin concentration that can occur at 9-ppn~ carbon monoxide for 8 hr or 35 ppm for 1 hr . (pp. 164-167 ~ The experimental studies on carbon monoxide health effects performed in recent years are summarized in Table VI]-5. They have tended to confirm the judgments expressed in the 1977 NRC report. Moderately severe exposure. to carbon monoxide--e.g., at 50 ppm for up to about an hour--can occur in kitchens as a result of ordinary use of a gas range, especially when the cooking utensil" divert or quench the flame. Higher exposures can be found indoor" in public buildings, such as ice-skating rinks, where mean concentrations of carbon monoxide as high as 100 ppn~ have been measured (Spengler, personal communication). The health effects of indoor exposures to carbon monoxide are addressed in the next section of this chapter, which deals with involuntary Smoking; carbon monoxide is, of course, a pollutant that is colon to cigarette-smoke and fossil-fuel combustion effluents. The effects of carbon monoxide from indoor combustion cannot be adequately assessed without considering the influence of exposure to cigarette smoke. For smokers, mainstream smoke is the dominant source of carboxyhemoglobin (COMb) in the blood. For nonsmokers, the lower COBb values can be attributed to metabolism, to carbon monoxide in the outdoor air, to carbon monoxide in sidestream smoke, and to carbon monoxide from indoor combustion sources. The extent of COHb saturation associated with metabolism is 0.~. Community air pollution or exposure to sidestream smoke can raise Comb in nonsmokers to 2_31.32 The influence of indoor combustion on Comb maturation depends on many factors. Carbon monoxide from indoor combustion may be dominant when there are no smokers in the occupied space and when outdoor carbon monoxide concentration is low. It can also be dominant even when cigarette use and outdoor concentration are high when the indoor combustion source ts large (as in the case of unrented space-heaters ) or when combustion eff iciency is poor because of poor burner maintenance or blockage of the air supply. A summary of measurements of indoor carbon monoxide concentrations is provided in Chapter TV. NITROGEN OXIDES Indoor combustion can have an important ef feet on the indoor concentrations of nitric oxide and nitrogen dioxide. Nitric oxide binds to hemoglobin JO produce me/hemoglobin. Many of the adverse effects reported in the past for carbon monoxide alone may be related to the combined action of COBb and me/hemoglobin, especially inasmuch

354 TABLE VII-5 Controlled Exposure to Carbon Monoxide Species Exposure Health Ef fects Observed Human ~ normal ~ 3 Human (n - 18~28 Human29 Hu - In (n - 19)37 Human (n - 20~43 H..~n44 Pigeon ~ nor~choles- terolemic and hy~er- cholesteroles~lc ~ Rabbit (hype~&holes- terolemlc) Dog (myoc'rdial in jury) Dog (anesthetlsed ~ S normal, open-cheated Monkey Rabbi t40 Rat (n - 8-16 )6 100 ppe, 1 h 200 ppe, 3 h 15-20 mg/m3, 1018 ppm, 30 d 10 eg/m3 9 Pam 90 d 50 pop, 4 h 150 ppm, 3.5 h 3.2-4.1: Hub 8X COHb 4. 92X COHb 150 pop, 52 and 84 we 250 ppm, 10 wk 100 ppm, 2 h 100 ppm, 2 h Mean exercise time until exhaustion signif icantly decreased No significant effect on acotopic sensitivity. reaction time, eye movements, visually evoked cortical potentials Increased albumin, B-globulins, total lipids, cholesterol, B-lipoproteins; decreased blood sugar None No signif leant changes in lung function No effect on critical flicker- fusion frequency; in monotonous situation, relative "activation" of sub Jective feelings Increased errors in auditory dis- crimination in open offices Less difficult task: no signifi- cant ef f ects in isolation booths Less difficult task: no signlfi- cant effectsa In hypercholesterolemic birds, atherosclerosis more severe Coronary arterial atheros clerosis signif icantly higher Decreased venticular fibrillation threshold Decreased venticular fibrillation threshold Ventricular fibrillation more easily induced 100 ppm, 6 ~ :; 9.3X (a',~`S COHb 180 Ape, 4 h Focal intimal edema in aorta 100 pp., 200 ppm, Changes in blood glucose and lactic 500 ppm; 4 h . acid; no significant plasma corticosterone increase Rat (n ~ 437 100-1,000 ppm, Lever-pressing response rate 1.5 h decreased at increasing concentra- tion Rat (exposed pee- lSO ppe, confine Reduced birthweight, decreased weight nasally) uous, IS% OOHb gain, lower behavioral activity, alte red central catecholamine activity, less total brain protein at birth aEnvironment and task difficulty may alter effects. bResponse decrease inconsistent at lower concentrations.

355 as sources that emit carbon monoxide often produce nitric oxide as well. If present data are indicative, nitric oxide at 3 ppm {3.75 mg/~3) is physiologically comparable with carbon monoxide at 10-15 ppm (11-17 mg/m3) . ~ Thus, NO'` may increase cardiovascular stress due to hypoxia, although the NOX does not shif t the oxygen binding equilibrium for hemoglobin, and the effects of NOX are not quantitatively identical. The work of Case et al. ~ has suggested that NOk generated by household combustion appliances accounts for a substantial fraction of the total methemoglobin present in the blood of most humans. NOx concentrations sufficient to generate 21 or more methemcglobin may be encountered often in the home (and in roadway tunnels).!. Nitrogen oxides may change heme by producing polycythemia with increased hematocrit and with decreased mean corpuscular volume. They may also produce leukocytosis and other hematologic abnormalities, as well as vascular membrane injury and leakage that lead to edema. '' Nitrogen dioxide exposure affects the activity of several enzymes: it decreases erythrocyte membrane acetylcholinesterase, increases peroxidized erythrocyte lipids, and increases glucose-6-phosphate dehydrogenase. It also produces substantial decreases in hemoglobin and hematocrit values. Both nitric oxide and nitrogen dioxide are formed from atmospheric nitrogen and oxygen in the high-temperature part of ~ flame by the temperature-dependent process of nitrogen fixation. Acute toxicity in not to be expected from the nitrogen dioxide formed in Invented indoor combustion, because not enough nitrogen dioxide is generated. But nitrogen dioxide concentrations equal to or greater than the current ambient-air quality standard of 0.05 ppm are not unusual in kitchens where gas Is used for cook ing (see Chapter IV) . At those concentrations, nitrogen dioxide may affect sensory perception, especially dark adaptation, 34 and produce eye irritation, especially with hydrocarbons . ~ ' Nitrogen dioxide can produce transient and long-term damage to both small bronchial airways and alveolar tissue. In the bronchial airways, exposure of rats to nitrogen dioxide at as low as 2 ppm for 4 h stimulated the differentation of conciliated cells into mature Clara cells and ciliated cells; I' that effect raises the possibility that chronic exposure could lead to chronic bronchitis. The nitrogen dioxide also destroyed Type ~ epithelial cells and stimulated the proliferation of Type II cells. Thus, chronic exposure might contribute to the development of emphysema. In addition, in animals challenged with bacterial aerosols after exposure to nitrogen dixoide at 1.5 ppm for 2 h or at 0.5 ppm for 2 wk. there was significantly increased mortality, compared with that in animal. challenged with the same bacterial aerosols without nitrogen dioxide. I' Further information on the acute and chronic toxicity of nitric oxide and nitrogen dioxide can be found in the 1977 NRC report on the nitrogen oxides and in the 1981 EPA criteria document on NO,`.42 Tables VII-6 and VII-7, from the NRC report, summarized observed effects of short-term exposures of humans to nitrogen dioxide at high and low concentrations. Table VII-8 summarizes some of the more recent exper imental exposure studies .

356 TABLE VII-6 Bump Effects of Acute Exposure to Blgh Nitrogen Dioxide Concentratlonsa Nitrogen Dioxide Concentration - ;~ig/m ppei 940 564 282 94 47 500 300 150 25 Clinical Effect Acute pulmonary edema fatal Bronchopneumonla--f anal Bronchiolitis fibrosa obUtera" fatal Bronchiolitis, focal pneu~tis-- recovery Bronchitis, bronchopneu - ala recovery aReprinted frog National Research Council.33(P. 269) Tine between Exposure and Terainatlon of Effect Wlthln 48 h 2-10 d 3~5 Dot 6-8 6-8 wit

357 TABLE VI I-7 Summary of Human Responses to Short-Term Nitrogen Dioxide j Exposures Alonea Ef feet - Nitrogen Dioxide Concont ration — c mg/2D~ ppm Time to Effect Odor threshold O. 23 0.12 Immediate Threshold for dark adapts- 0.14 O. 07S Not reported tion 0. 50 O. 26 Not reported Increased airway 1. 03. 8 O. 7-2. 0 20 ~ nb resistance 3. 0-3. 8 1. 6-2. 0 IS min 2.8 1.5 45 sync 3.8 2.0 45 mind 5.6 3.0 AS mine 7. Sag. 4 4. 0~5. 0 40 mint 9.4 S. 0 15 min 11.075.2 6.0-40.0 5 min 13.2-31.8 7.017.0 10 ming Decreased pulmonary 7. 5-9. 4 4. 0-5. 0 15 min dif f us ing capaci ty Increased alveolar 9.4 5.0 25 minh arterial PO2 dif ference No change in sputum 0. 9-6. 6 O. 5-3.0 45 min histamine concentration aReprinted from National Research Council. 33 bExposure lasted 10 min. Ef f set on flow resistance was observed 10 min af ter termination of exposure. CEffect was produced at this concentration when normal subjects and those with chronic respiratory disease exercised during exposure. dEffect occurred at rest in subjects with chronic respiratory disease. eEffect occurred at rest in normal subjects. fExposure lasted 10 An. Maximal effect on flow resistance was observed 30 min later. "Also failed to find increased flow resistance over the range of nitrogen dioxide exposures from 5. 1 to 30. 1 mg/m ~ 2. 7-16. 0 ppm) . hEffect occurred 10 min after termination of 15-min exposure.

358 TABLE ~JII-8 Controlled Exposure to Nitrogen Oxides Species Exposure Mouse (6-8 wk old)l9 NO, 10 ppm, ~ hid, ~ d/^, up to 30 wk NO, 10 ppm Mouse27 NO , 0. S-28 Ape, Mao to lyr Guinea pig25 NOx. 1 ppm, 6 mo Han (asthma, n - I]~ NO2, 0.5 ppa, 2 h bronchitis, n ~ 7) Human ~ aroma, NO2, 0. 1-0. 2 pop Health Ef fects Observed Lung damage, suppressed immune function wi Oh chronic exposure, enhanced immune reactivity with shorter exposures Paraseptal emphysema, suppressed immune function with chronic exposure, enhanced immune reactivity with shorter exposures Mortality after Streptococcus pyogenes, mortality increased with increasing dose and exposure time Disturbed glycolysis, enhanced catabolic processes in brain, inhibited respira- tion, decreased brain aminotransferase activity, morphologic alterations in blood vessels Lightness in chest, burning of eyes, headache, or dyspnea; pulmonary- funct ion changes; nasal discharge Increased bronchoconstrictiona cat26 NO2, 80 pap, 3 h Diffuse alveolar damage Guinea pig41 NO2, 0.506 ppm; NO, 0.05 ppm; 122 d Mousel2 NO, 1.5~5.0 pop, ~ h Mouse 38 Hameter24 aCarbachol provocations In lungs: decreased phosphatidyl- ethanola~ rue, sphingomyelin, phosphati- dyl serine, phosphatidi c acid, phosphatitylglycerol 3~phosphate; increased lysophosphatidylethanolamine Mortality in mice challenged with Streptococcus aerosol significantly increased at 2.0 ppm and above NO2, 0. ~ ppm; 10, Average protein content of lungs 12, 14 d significantly higher NO2, 30 ppm' 3 wk Loss of body weight, increased dry lung weight, decrease in lung elastin and collagen melanin and collagen later returned to normal.

3s9 The evidence of health effects after prolonged exposure at low concentrations is inconsistent. This should not be surprising, in that much of the evidence was obtained from epidemiologic studies in which the observed effects could have been due to the presence of other air pollutant. or to their combined effects with nitrogen dioxide. The 1977 NRC report summarized the effects of exposure to NOx at low concentrations on respiratory function and disease as follows: 33 Two epidemiologic studies suggest that the combination of nitrogen dioxide at concentrations of 0.15 to 0.3 mg/~3 (0.08 to 0.16 ppm) with other pollutants causes changes in ventilatory function. Two other studies in which lower levels of nitrogen dioxide were studied did not reveal these effects. Because of the disparity in populations and in pollutant conditions, conclusions cannot be reached regarding the effect, if any, of chronic exposure to nitrogen dioxide on rentilatory function. Some epidemiologic data support the idea that excess acute respiratory disease may occur in healthy populations following exposure to atmospheres containing nitrogen dioxide. Four studies have been reviewed in the search for an association between exposure to ambient concentrations of nitrogen dioxide from 0.10 to 0.58 mg/m3 (0.053 to 0.309 ppm) and small excesses in respiratory illnesses. However, the variable pollutant exposures and conditions of study make it difficult to quantify the relationship of nitrogen dioxide by itself to the reported increases in respiratory disease. In each study air contaminants likely to enhance susceptibility to respiratory infection (sulfur dioxide, sulfuric acid, sulfates, nitrates, etc.) were also present. Evidence that nitrogen dioxide induces excess chronic r aspiratory disease is not convincing . Reports of excess chronic respiratory disease associated with low concentrations of ambient nitrogen dioxide (~.10 mg/~3~0.053 ppm] ~ do not provide convincing evidence that other pollutants that were measured at relatively high concentrations were not the probable cause of the excess disease. In the presence of low concentrations of sulfur dioxide and particulates, three investigators failed to detect excess chronic respiratory disease in areas where nitrogen dioxide exposure" were <0.10 mg/~3 (0.053 ppm). (pp. 271-272) SUMMARY OF RECENT EPIDEMIOLOGIC STUDIES OF Ir8)ooR POLI,UTION WITH SPECIAL REFERENCE TO NOX EXPOSURE The availability of inexpensive passive-diffusion-tube samplers for nitrogen dioxide has stimulated a 'series of studies of indoor nitrogen dioxide pollution effects in the United States and the United Kingdom. Melia et al. 3i studied the relation between respiratory illness _ ~ in pr imary-school children and the use of gas for cooking . In a 5-yr

360 longitudinal study of schoolchildren in England and Scotland, 4,827 boys and girls aged 5-10 yr in 27 randomly selected areas were examined in 1977, the last year of the study. me authors reported that prevalence of one or more respiratory 83~Aptall8 or diseases W-8 higher in children from gas~cooking homes than in those from electric~king homes and that the association appeared to be independent of age, sex, social class, number of cigarette- - okere in the hoe, and latitude. However, it was found only in urban areas {for boys, EN < 0.005, for girls, Ed. ~ 0.08~. In children aged 6-7.5 ye in 1973 who were followed until the last year of the study, there was Bode indication that the association between respiratory illness and gas cooking disappeared as the children grew older; this trend was not obvious in the children in the other age groups, who were follwed for 2-. ye. The evidence from the 1977 study did show a relationship between gas cooking and respiratory illness that supported results of the 1973 study in the same group, although the results on cohorts showed Bane indication that the relationship may disappear as children grow older. Florey et al. 15 examined the relation between lung function and respiratory illness in a population of 808 primary-achool children aged 6-7 yr and the concentrations of nitrogen dioxide in the kitchens and bedroom of their homes. Complete cats were collected on about 661 of the population. The children lived in a defined 4_km2 ares in MiddleaDorough (United Kingdom). One-week average outdoor nitrogen dioxide concentrations varied little over the ares: 25-43 ug/m3 (14-24 ppb). The prevalence of respiratory illness was higher in children from gas-c~king than from electric~cooking homes (p ~ 0.l). Although prevalence was not related to kitchen nitrogen dioxide concentration (9-570 ug/m3), tt increased with increasing nitrogen dioxide in the children's bedrooms in gas-cooking homes (4-169 ppb; p ~ 0.~. Lung function was not related to nitrogen dioxide content in the kitchen or bedroom. Because of the very low nitrogen dioxide concentrations at which an association with illness was observed and the inconsistency between these results in the United Kingdom and those from several studies in the United States, the authors speculated that the nitrogen dioxide concentrations were a proxy for some other factor more directly related to respiratory disease, such as temperature or humidity. A similar study by Reller et 81.21 in Columbus, Ohio, failed to establish any increase in respiratory disease or decrease in pulmonary function (F\tC and F~ro.7s) associated with the use of gas for cooking. Their sable included 441 families, divided into twO groups: those using gas and chose using electricity in cooking. Family health and demographic data were obtained from the participants. Reports of acute respiratory illness were obtained through biweekly telephone calls to each household. Respondents were asked to report respiratory illness in any member of Me household and to indicate the presence or absence of ~ set of signs and symptoms. Ambient air was analyzed indoors and outdoors in ~ sample of the households, and pu~nary- function tests were conducted on a subs~ple of the participants representing both types of households. The mean nitrogen dioxide concentrations were 0.05 ppm (90 ug/~3) in the ges~cooking homes

361 and O.03 ppm (SO ~/m3) in the electric-cooking homes. In an extension of this study, Keller et al.22 selected 120 households with achool-age children from the gas-cooking and electric-cooking cohorts. Reports of respiratory illness and symptoms were obtained by telephone interview every 2 wk for 13 mo by a nurse-epidemiologist. If the onset of respiratory illness occurred within 3 d of the call, a household visit was arranged to examine the person reported ill and to obtain a throat culture. In addition, two set. of ~well. controls were examined. The results validated the reporting method and replicated earlier findings of no significant difference in incidence of acute respiratory illness between gas- and electric-cooking households. The largest and most recently reported study of the effects of gas cooking on the health of children is that of Speizer et a1.~' As part of a long-range prospective study of the health effects of air pollution, they studied approximately 8,000 children aged 6-10 yr in six communities. Questionnaires were completed by their parents, and simple spirometry was performed in school. Comparisons were made between children living in homes with gas stoves and those living in honked with electric stoves. Children from households with gas stoves had a greater history of respiratory illness before age 2 (average difference, 32 . 5/l, 000 children ~ and small but signif icantly lower EEV and PVC values corrected for height (average difference, 16 m1 and 18 ml, respectively) . These f indings were not explained by differences in social class or in parental smoking habits. Measurements taken in the homes for 24-h periods showed that nitrogen dioxide concentrations were 4-7 timer higher in homes with gas stoves than in homes with electric stoves. However, these 24-h measurements were generally well below the current federal 24-h outdoor standard of 100 ~g/m3. Short-term peak exposure", which were in excess of 1,100 ~/m3, occurred regularly in kitchens. Further work will be required to determine the role of these short-term peaks in the effects noted. REFERENCES 4. 1. American Industrial Hygiene Association. Hygienic guide eerie-. Carbon monoxide. Am. Ind. Hyg. Assoc. J. 26:431-434, 1965. 2 . Armitage, A. E., R. F. Davies , and D. M. Turner. The effects of carbon monoxide on the development of atherosclerosis in the White Carneau pigeon. Atherosclerosis 23:333-344, 1976. a. Aronow, W. S., and J. Cassidy. Effect of carbon monoxide on maximal treadmill exercise: A study in normal persons. Ann. Intern. Hed. 83: 496-499, 1975. Aronow , W . S ., E . A . Stemmer , B . Wood , S . Zweig , R . Tsao , and I, . Riggs. Carbon monoxide and ventricular fibrillation threshold in dogs with acute myocardial injury. Am. Heart J. 95:754-756. 197B. 5. Aronow, W. S., E. A. Stemmer, and S. Zweig. Carbon monoxide and ventricular fibrillation threshold in normal dogs. Arch. Environ. Health 34:184-186, 1979.

362 6. Atland, P. D., and B. A. Rattner. Effects of nicotine and carbon monoxide on tissue and systemic changes in rats. Environ. Res. 19:202-212, 1979. 7. Ator, N. A., W. B. Merigan, Jr., and R. W. McIntire. The effects of brief exposures to carbon monoxide on temporally differentiated responding. Environ. Res. 12:81-91. 1976. 8. Case, G. D., J. S. Dixon, and J. C. Schooley. Interactions of blood metalloproteins with nitrogen oxides and oxidant sir pollutions. Environ. Res. 20:43-65, 1979. 9 . Case , G . D ., J . C . Schooley , and S . D. Jonathan . Uptake and Metabolism of Nitrogen Oxides in Blood. Paper presented at the 20th Annual Meeting of the Biophysical Society, Seattle, Washington, February 24-27, 1976. 10. Davies, R. F., D. L. Topping, and D. M. Turner. The effect of intermittent carbon monoxide exposure on experimental atherosclerosis in the rabbit. Atherosclerosis 24:527-536, 1976. 11. DeBias, D. A., C. M. Banerjee, N. C. Birkhead, C. B. Greene, S. D. Scott, and W. V. Earrer. Effects of carbon monoxide inhalation on ventricular fibrillation. Arch. Environ. Health 31:42-46, 1976. 12. Ehtlich, R., J. C. Findlay, J. D. Fenters, and D. E. Gardner. Bealth effects of short-term inhalation of nitrogen dioxide and ozone mixtures. Environ. Res. 14:223-231, 1977. 13. E`rans, M. J., and G. Freeman. Morphological and pathological effects of NO2 on the rat lung, pp. 243-26S. In S.D. Lee, Ed., Nitrogen Oxides and Their Effects on Bealth. In Arbor, MiCh.: Ann Arbor Science Publishers, Inc., 1980. 14. Fechter, L. D., and Z. Annau. Toxicity of mild prenatal carbon monoxide exposure. Science 197:680-682, 1977. IS. Florey, C. du V., R. J. W. Melia, S. Chinn, B. D. Goldstein, A. G. F. Brooks, B. B. John, I. B. Craighead, and X. Webster. The relation between respiratory illness in primary schoolchildren and the use of gas for cooking. III. Nitrogen dioxide, respiratory illness and lung infection. Int. J. Epidemiol. 8:347-353, 1979. 16. Gardner, D. E., F. J. Miller, E. J. Blommer, and D. L. Coffin. Influence of exposure mode on the toxicity of NO2. Environ. Health Perepect. 30: 23-29, 1979 . 17. Goldemith, J. R. and L. T. Friberg. Effects of air pollution on h''--n health, pp. 458-611. In A. C. Stern, Ed. Air Pollution. 3rd. ed. Vol. II. The Effects of Air Pollution. New York: Academic Preps, Inc., 1977. 18. Bollowell, C. D., R. J. Budnitz, C. D. Case, and G. Traynor. Combustion Generated Indoor.Air Pollution: Field Studies 8/75-10/75. Lawrence Berkeley Laboratory Publ. LBm4416. Berkeley, Cal.: Lawrence Berkeley Laboratory, 1976 . 19. Molt, P. G., L. M. Finlay~ones, D. Reast, and J. M. Papadimitrou. Immunological function in mice chronically exposed to nitrogen oxides (Ned ~ . Environ . Res . 19 :154-162, 1979 . 2 0 . Bugod , C ., L . H . Eswk ins , and P . Astrup . Exposure of pass ive smokers to tobacco smoke constituents. Int. Arch. Occup. Environ. Health 42: 21-29, 1978.

363 21. Keller, M. D., R. R. Lane~e, R. ~ . Mitchell, and R. W. Cote. Respiratory illness in households us ing gas and elects icity for cooking . I . Survey of incidence. Environ. Res . 19: 495-503, 1979 . 2 2. Keller, M. D., R. R. Lane~e, R. I . Mitchell, and R. W. Cone . Respiratory illness in households using gas and electricity for cooking. II . Symptoms and objective f indings . Environ. Res . 19: 504-51S, 1979 . 2 3. Kerr, ~ . D ., T. J . Kulle, M. L. Mcilhany, and P. Swideraky. }if feats of nitrogen dioxide on pulmonary function in human subjects: An environmental chamber study. Environ. Res. 19:392-404, 1979. 24. Eleinerman, J., and M. P. C. Ip. Effects of nitrogen dioxide on elastin and collagen contents of lung. Arch. Environ. Bealth 34: 228-232, 1979. 25. Provider, S., A. Mis~ewicz, and J. Pastewicz. Effect of binding of nitrogen oxides with gaseous anusonia on the occurrence of changes i n the central nervous system. Neuropatol pal . 12: 413-426, 1974 . ~ in Polish; English summary ~ 2 6. Langloss, J. M., E. A. Hoover , and D. E. Kahn. Diffuse alveolar damage in cats induced by nitrogen dioxide or Feline Caliciviru~. Am. J. Pathol. 89: 637-648, 1977. 27. Larsen, R. I., D.-E. Gardner, and D. L. Coffin. An air quality data analysis system for interred sting effects, standards, and needed source reductions: Part 5. NO2 mortality in mice. J. Air Pollut. Control Ascot. 29:133-137, 1979. 28. Luria, S. M., and C. L. McKay. Effects of low levels of carbon monoxide on vis ions of smokers and nonsmokers . Arch . 13n~riron . Health 34: 38-44, 1979. 29. Markaryan, M. V., T. A. Smirnova, and 0. S. Rhokhlova. Effect of chronic exposure to carbon monoxide on the biochemical composition of human blood. Kosm. Biol. Aviakosm. Hed. 11~4) :46-SO, 1977. (in Russ fan; English summary ~ 3 0 . Melia, R. J . W., C . du V. Florey, D. G . Altman , and A. V. Swan . Association between Gas cooking and respiratory disease in children. Br. Med. J. 2 :149-152, 1977. 31. Melia, R. J. W., C. do V. Florey, and S. Chinn. The relation between respiratory illness in primary schoolchildren and the use of gas for cooking. T. Results from a national survey. Int. J. Epidemiol . 8: 333-338, 1979 . 32. National Research Council, Committee on Medical and Biologic Effects of Environmental Pollutants. Carbon Monoxide. Washington, D.C.: National Academy of Sciences, 1977. 239 pp. 33. National Research Council, Committee on Medical and Biologic Ef feats of En~rironmenta1 Pollutants . Nitrogen Oxides . Washington, D.C.: National Academy of Sciences, 1977. 333 pp. 34. National Research Council, Committee on Medical and Biologic Effects of Environmental Pollutants. Vapor-Phase Organic Pollutants. Volatile Hydrocarbon'; and Oxidation Products. Washington, D.C.: National Academy of Sciences, 1976. 411 pp. 35. Orehek, J., J. P. Massari, P. Gayrard, C. Grimaud, and J. Charpin. Effect of short-term, low-level NO2 exposure on bronchial sensitivity of asthmatic patients . J. Clin . Invest. 57: 301-307, 1976.

364 36. Posin, C., R. Clark, M. P. Jones, J. V. Patterson, R. D. Buckley, and J. D. Hackney. Nitrogen dioxide inhalation and hen blood biochemistry. Arch. Environ. Bealth 12s318-324, 1978. 37 . Raven, P . B., J. A. Gliner , and J . C . Sutton. Dynamic lung function changes following long-term work in polluted environments. Environ. Res. 12 :18-2S, 1976. 38. Sherwin, R. P., and L. J. Lisyfield. Protein leakage in the lunge of mice exposed to O.S ppa nitrogen dioxide. A fluorescence assay for protein. Arch. environ. Besith 31 Il6-~18, 1976. 39. Speizer, F. E., B. Ferris, Jr., Y. M. M. Bishop, and J. Spengler. Respiratory disease rates and pulmonary function in children striated with NO2 exposure. Am. Rev. Respir. Dis. 121:3-10, 1980. 40. momsen, B. R., and R. Rjeldsen. Aortic intimal injury in rabbites An evaluation of a threshold limit. Arch. Environ. Bealth 30:604-607, 1975. 41. Trzeciak, B. I., S. R ~ ider, R. Rryk, and A. Rryk. The effects of nitrogen oxides and their neutralization products with ammonia on the lung phospholipids of guinea pigs. Environ. Res. 14:87-91, 1977. 42. U.S. Environmental Protection Agency. Air Quality Criteria for Oxides of Nitrogen. Research Triangle Park, N.C.: U.S. Environmental Protection Agency, Environmental Criteria and Assesment Office, 1981. (in press) 43. Weber, A., C. Jemini, and E. Grandjean. Effec:t. of low carbon monoxide concentrations on flicker fusion frequency and on subjective feelings. Int. Arch. Occup. Environ. Health 36: 87-103, 1975. (in German; English summary) 44. Wright, G. R., and R. J. Shephard. Carbon ~nonoxide exposure and auditory duration discrimination. Arch. Environ. Bealth 33:226-235, 1978. IN\tOI~UNTAR1r SHOEING The combustion of tobacco products is responsible for only a Ball fraction of the total atmospheric pollution,.. and it is only in the enclosed indoor environment that Poking produces a major fraction of the airborne environmental contamination. me potential health effects of this contamination have recently becase a subject of considerable concern and contro~reray..' '. c`(pp.ll-l--ll-4l} s. The health effects of poking on pokers have been extensively studied..' But the health effects on nonsmokers have received far lese study, and th4~- section documents what is known about these effects. me exposure of nonsmokers to envirormental contamination by the combustion products of tobacco has been referred to as Impassive ~king,. Second-hand ~king,. and ~in~roluntery ~king.. He use the tem involuntary ~king. for this kind of exposure, it provides exposure to many of the same constituents of tobacco smoke that voluntary smokers experience, and it i. involuntary, in that the exposure occurs as an unavoidable <:onsequence of breathing in smoke~f illed roar.

365 The chemical constituents found in the atmosphere due to tobacco stoke are derived from two sources--mainstream and side$tream smoke. Mainstream smoke emerges from the tobacco product after being drawn through the tobacco during puffing. Sidestream Invoke rises from the burning cone of tobacco. For several reasons, mainstream smoke and sidestream smoke contribute different concentrations of many substances to the atmosphere: different amount. of tobacco are consumed in the production of mainstream and sidestream invoke; the temperature of combustion for tobacco is different during puffing and during smoldering; and some substances are partially absorbed from the Minstrel Make by passage through the cigarette and the lungs of the smoker. The amount of a substance absorbed by the smoker depends on the characteristics of the substance and the depth of inhalation by the smoker. When the smoker does not inhale the smoke into his or her lungs, the smoke exhaled contains less than half its original amount of water-soluble volatile compounds, four-fifths of the original non~water-soluble compounds and particulate matter, and aln~s~c all the ^= rarer' m^~^Y~ ~^ 2 ~ therm - ~^ omen - I ~ ^~. 1 ~ - ~^ ~. i ^~ - ~^ ~,,w,. ... ,,,_. _w~ ^~-~_= --lo I"~-~so -flow" .~~ r that exhaled into the atmosphere contains less than one-seventh of the original amount of volatile and particulate substances and less than half the original concentration of exhaled carbon monoxide.22 The differential impact of these factors on the extent of contamination is discussed elsewhere in this report. The differences in chemical composition between sidestrean' and mainstream spoke and the differences between the low~dose, continuous exposure of the involuntary smoker and the high~dose, intermittent exposure of the voluntary smoker make the comparison of dosage in terms of Cigarette equivalents ~ highly Speculative . The qualitative and quantitative differences between the two kinds of exposures prevent the extrapolation of the well-established health effects of cigarette-amok ing to the involuntary smoker . We therefore try to identify health effects on the basis of actual exposures, rather than on the basis of effects on smokers. ABSORPTION OF SMOKE CONSTITUENTS There are no direct measurements of absorption of most of the constituents of tobacco Smoke. However, Bugod et al.2' found that the concentrations of carbon monoxide, nitric oxide, acrolein, hydrogen cyanide, and nitrogen dioxide in a sealed chamber decreased when nonsmokers were present, but not when the chamber was empty; hence, either absorption by the nonsmokers or adsorption onto their clothing occurs. A number of studies that have examined carbon monoxide absorption are summarized in Table vII-9. Carbon monoxide is often used as a measure of tobacc~"moke pollution and absorption, because it is readily measured and has been implicated in the pathogenesis of atherosclerosis. But there are several problems in the use of carbon monoxide as a measure of total smoke exposure. Smoking is only one source of carbon monoxide in the environment and great care must be taken to establish that the carbon monoxide measured is indeed from

366 1 1 ~ ~ e ~ ~ 0 ~ `,` ~ ~ ~ ~ ~ 0 to o Cl ~ of ~ ~ ~ 4U O ~ O ~L' ~ ~ 4, ~ ~ ~ _ U' (U ~ ~ ~ .. O , Os ~ ~ O ~ 8 0° ~ O 8 s a` s 6 o y o e O A` O ,, O 4~ a: ~ ~ o ~ ~ ~ Z z z O E z ~ z e At 0 x ~ 0 ~ -it C: ~ it ~ ~ ~ ~ 8 c _ ~ V ~ ~ Cat — l: ~ · O ~ 1 1 0 V ~ ~ _ ~ Cal ~ ~ US c: ~ :: ~ . ° ~ 0 ~ ~ I ~ ~ ° 8 ° cat ° c ~3 e c o' ~ ~ ~ ~ ~ ~ C ~ 0 ~ ~ 0 0 ~ ~ ~ ~ ~ ~ ~ V V V :> 0 :, ~, ~ v V 4? - ~ ~ V V e: O ~ ~ ~ ~ V ~ ~ ~ ~ dV O ~ C~ ~ ~ t~_' oo _ oo oo Do ~ ~ ~ V tl. ~ seS a0= ~ ~ ~ e ~ v ~ ~ ~ O D V ~ V ~ ~ ~ ~ ~ ~ e o ~ ~ ~ I ~ E O O O 0 ~S ~ ~ ~ 1 U~ cn _ _ ~: o qla O O V ~C ~ ~ S V U. V C ~ · ~ C C~ O ~ · ~ 0 1 1 ~ O . ~ ~o _ 2 ~ 1 1 Z o C~ 1 —~ I _ ~ ~ ~ ~ ~ V ~ ~ C ~ ^R 0 ~ o j ~ 8 l: · _. V ~ O `: O O O ~:t C ~ ~ v D t_ 0 ~ ~ ~ ~ 3 45 ~ ~ ~ _ _ _ ~ ~ V ~ ~ ~ _ V :: ~ ~ _d V ~ V =a ~ — Z o o O V ~ "= ~ _ O o~ 0 0 m 0 ~ 0 ~ a ~ ~ ~ ~ 0 ~

367 1 1 .^ _. .- e O ~ r ~ ~ ~ ~ 0 ~ } ~ c 0 ~ Is = 0 = e ~ ~ 0= ~ 0= e ~ ~ 6 ~ ~ I ~ C ~ ~ ~ C O ~' o o^ o O O 1 1 3 :^ 1 v _ ClO ~ ~ o D _ CL ~ ~ ~ O ~ ~ ~ ~ _1 V ~ _ t' 0 I, ~ V S E ~ ~ e o ~ ~ ~ L - ~ ~ ~ %~ c ~ ~ ~ ~ ~ C o z z 1 z ° I 1 +^ 0 US He E ,13 4, He me I ~ · — ~ O ~ TO If D 3 ~ e E h O lo, ~ o S" ~0 at: V - C) Ct

368 cigarette smoke. Carbon monoxide is part of the gas phase of smoke and so does not nettle out of the atmosphere passively, but is quite avidly absorbed f ram the atmosphere by breathing . As a result, the time course of carbon monoxide concentration differs from that of the particulate phase of the smoke, and the impact on carbon monoxide of f filtration, ventilation, and number of persons in the room is also different from the impact on particulate constituents. Because carbon monoxide ts bound to hemoglobin with 210 ti'ses the affinity of oxygen, very low concentrations of carbon monoxide in the air can result in substantial carboxybemoglobin {COHb) concentrations in the blood. A small amount of carbon monoxide is produced by the body, resulting in COBb content of approximately 0.7%. C - b values are about the same in rural communities' and increase to about 2.5-31 when there is marked Invoke pollution. Two studies examined carbon monoxide absorption by nonsmoking workers under conditions where smoking was allowed as part of the normal work environment. Szadkowski _ al. s. found very low concentrations of carbon monoxide in an office setting and no change in COMb. Seppinen and UusitaloS ~ found higher carbon monoxide content in restaurants and offices (2.5O15 ppm) and still no change in COlIb, but the workers began the day with COMb concentrations (2.1~) comparable with tbose that would be expected from such atmospheric carbon monoxide content and therefore would not be expected to change. A number of studies have documented increases in COHb secondary to smoke exposure under experimental conditions {see Table ire I-9 ), and the g reates t extent of smoke pollution that would normally be tolerated produces COMb of approximately 2.5-3% after 1-2 h. SrchS. found COMb of 5S in nonsmokers, but there was more smoke than would be tolerated under normal conditions. Russell _ al. .. 45 also measured nicotine excreted by nonsmokers and found that they absorb measurable amounts of nicotine from the environment, but only 6 . 5% of that absorbed by smokers . Repace and Lowrey ~ 2 estimated the exposure of nonsmokers to respirable suspended particles from cigarette smoke. They predicted that a nonsmoker working in an office where Poking was allowed would inhale particles at a rate 3 times greater than without this exposure. In suanary, the literature suggests that nonsmokers would be expected to have slight increases in their COMb content (1-2%) from cigarette smoke in the normal working environment and more {2-3%) under conditions of heavy smoke pollution. Nonsmokers also absorb nicotine and an unknown quantity of tether smoke constituents. EFFECTS ON HEALTEY PERSONS The effect of involuntary smoking on a person is determined not only by the qualitative and quantitative aspects of the smoke-filled environment, but also by the characteristics of the person. Reactions may vary with age and with the sensitivity of a person to the components of tobacco smoke.

369 Annoyance In 197S, a national probability sample of U.S. telephone households3S was asked to agree or disagree with the statement, .It is annoying to be near a person who is smoking cigarettes.. Among Uneven pokers, ~ 77% of the males and 80.5% of the females agreed with the statement; among current smokers, 35% of the males and 34 . S% of the females also agreed with the statement. Several federal agencies '2 cooperated to survey the symptom experienced by travelers on military and commercial aircraft. They distributed a questionnaire to passengers on 20 military and eight commercial flights; 57% of the passengers on the military flights and 458 of the passengers on the commercial flights were smokers. The planes were well ventilated, and carbon monoxide content was always below 5 ppm, with low concentrations of other pollutants as well. In spite of the low measurable pollution, over 60% of the nonsmoking passengers and 1S-22% of the smokers reported being annoyed by the other passengers' smoking. These feelings were even more prevalent among nonsmokers who had a history of respiratory disease. Seventy-three percent of the nonsmoking passengers on the commercial flights and 629e of the nonsmoking passengers an the military flights ~ ugges ted that some remedial action be taken; 84% of those who suggested remedial action felt that segregating the smokers f tom nonsmokers would be a -satisfactory solution. Such segregation is now required on commercial aircraft. The annoyance reaction maybe due to the odor, probably attributable to both the particulate and vapor phases; the odor threshold appears to be low. ~ ~ ~ ~ ~- Irritation l Many of the substances in cigarette smoke are irritating; the major sites of irritation are the eyes and nasopharynx. Speer s ~ assessed the nature of this irritation by interviewing 250 nonallergic patients about their reaction to cigarette Smoke; 69.2% reported eye irritation, 31.6% headache, .29.2% nasal symptoms, and 25.2% cough. Barad ~ ~ surveyed 21,366 employees of the Social Security Administration and found that nonsmoking workers reported high prevalences of conjunctival irritation (47.79~), nasal discomfort (34.7~), and cough, core throat, or sneezing (30 . 3% ~ when exposed to cigarette smoke . Weber et al.6S 66 exposed subjects to various concentrations of c igarette smoke in a sealed chamber and noted that ache eyes were most sensitive to the irritants in the smoke, followed by the nose. Self-reported eye irritation was closely related to such objective signs as tear flow and eye closing or rubbing. Annoyance was the came for pollution caused by whole smoke and by only the gas phase; that indicates that it is the gas phase that is annoying. But whole smoke produced considerably rove irritation as expressed by eye and nose symptoms, and that indicates that Me particulate phase is responsible for irritation. Bugod et al. 28 confirmed that the eyes are the most

370 sens it ire site and found that acrolein at the concentration" found in smoke-filled environments did not cause significant irritation. Artho and Koch' have reported 11 unpleasant-smelling constituents in the volatile phase and 50 in the semivolatile phase of cigarette smoke. The eye and nose irritation experienced by nonsmokers in a smoke-filled environment is influenced by the humidity of the air, as well as by the concentration of irritating substances. Johansson 2 ~ and Johansson and Ronge3° have shown that eye and nose irritation due to cigarette smoke is maximal in warm, dry air and decreases with a small rise in relative humidity. Physiologic Responses to Smoke At Rest. Harke and Bleichert 2 S studied 18 adults (11 smokers and seven nonsmokers) in a 170-~ room in which 150 cigarettes were smoked or allowed to burn in ashtrays for 30 min. They noted that the subjects who smoked during the experiment had ~ significant lowering of skin temperature and a rise in blood pressure. Nonsmokers who were exposed to the same smoke-contaminated environment showed no change in either of these measures. Loquette et al. performed a similar experiment with 40 children exposed alternately to smoke-contaminated and clean atmospheres, but otherwise under identical experimental conditions. Exposure to the smoke was associated with increases In heart rate (5 beats/min) and in systolic and diastolic blood pressure (4 and 5 mm Hg, respectively). The differences in results between these studies may be due, in part, to the age of the subjects: children may be more sensitive to the cardiovascular effects of involuntary smoking than adults. Or the increases in heart rate and blood pressure may be due to a difference between children and adults in the psychologic response to being in a smoke-filled atmosphere. Pimm et al. ~ found a slight decline in heart rate in control subjects of both sexes (thought to be secondary to prolonged inactivity) and a similar decline in heart rate in males exposed to cigarette smoke. However, women exposed to smoke had a small but significant increase in resting heart rate. The authors suggested that this may be due to a difference in psychologic, rather than physiologic, response in the women. Rappel et a1.~' examined this question with a group of 56 student. exposed to cigarette smoke. There was a slight increase in the entire group in systolic blood pressure on exposure to smoke. When the group was divided into those who were indifferent to cigarette smoke and those who expressed a dislike for it, both groups again had a r ise in systolic blood pressure on exposure to smoke, but the ~dislike. group also had a significantly higher heart rate at the start and during the entire course of the studys that suggests that psychologic factors may play a role in the physiologic response to involuntary smok ing . Pimm et al. 38 examined the effect of exposure to machine-produced smoke on ventilatory function in healthy young adults. There were no significant changes in the subdivisions of lung volume, maximal

371 expiratory flow volume, or single-breath nitrogen washout after exposure. With Exercise. Several authors have found small decrements in maximal aerobic capacity at COHb contents corresponding to those associated with involuntary stokings ~ 2 ~ ~ ~ for a given degree of exercise, there are reductions in exercise time to exhaustion and maximal oxygen consumption, and there is a higher heart rate. These effects were more pronounced in older than in younger subjects. Gliner et al. 23 evaluated submaximal exercise and found no change with COBb at 3-6%. Pimp et al. ~ evaluated young adults after exposure to cigarette smoke for 2 h (COHb, 1%) and found no change with submaximal exercise. Shephard et al. S2 studied 23 healthy young adults after 2 h of passive smoke exposure with intermittent bicycle ergometer work sufficient to increase respiratory minute volumes by a factor of 2.5. Carbon monoxide equivalents of 20 ppm and 31 ppm did not change static lung volumes and produced small changes (3-4% ~ in FVC, FE`t, Vmax 50%, and Vmax 75%, equivalent to cigarette consumption of less than 0.5 cigarette in 2 h. Psychomotor Function There has been some concern over the ef feats of relatively low concentrations of carbon monoxide on psychomotor functions (which involve perception of and reaction to stimuli ), especially those related to driving an automobile. There is an extensive and sometimes contradictory literature on this subject; but it is beyond the scope of this report, and the reader is referred to several recent reviewR.3~ 36 l' Most of the documented effects occur at COMb concentrations well above those produced by involuntary amok ing; however, slight changes in acoustic and visual vigilance have been reported at COMb as low as 2~. The impact of these changes on complex functions such as driving, and their interactions with fatigue and alcohol have not been.evaluated for COHb in the range of 2-3%. Lonn-Term Ef f eats The question of long-term effects on the nonsmoker of exposure to cigarette smoke has only recently been raised. The difficulty of measuring the exposure, the complex interaction of cigarette-~moking with behavioral and socioeconomic factors, and the problem of controlling for past smoking history, air pollution, and industrial exposure mace it very difficult to isolate the effect of cigarette smoke on the nonsmoker. Recent population studies that accounted for these confounding factors indicated that passive smoke exposures are associated with increased incidences of respiratory mechanical function abnOr~aiitieS. 27 lo .e White and Froeb ~ examined the relationship of exposure to cigarette Make in the workplace and tests of lung function. They

372 found that nonsmokers who had worked where Booking was allowed had unad justed midexpiratory (FEF 25-751 ) and end-expiratory (F8F 75-85%} flow rates lower than those of workers in workplaces where smoking was restricted, but not significantly when adjusted for Rex, age, and height. They suggested that the differences represent small-airway dysfunction produced by smoke exposure. and small-airway dysfunction ts thought to be an early precursor of clinically significant chronic obstructive lung disease. They controlled for occupational and air-pollution exposure and for asking in the hare. It is difficult to procure an association from a single Study, especially in a subject as complex as involuntary Invoking; however, their data do suggest tot exposure to cigarette Smoke may have a deleterious effect on the health and function of the healthy nonsmoker in the work environments ~ _ Hirayams,~7 in a study of mortality records in 29 health~center districts in Japan, followed 91,540 nonsmoking wives, aged 40 and above, for 14 yr (1966-1979) and assessed the standardized mortality rates for lung cancer according to the smoking habits of their husband-. Wives of heavy smokers (greater than 20 cigarettes/d) were f ound to have a relative r isk of developing lung cancer of 2 . I, whereas wives of ex-sn~okers and of smokers of fewer than 20 cigarettes/d had a relative risk of 1.6. The relation between ~ husband's smoking and a wife's risk of developing lung cancer showed a similar pattern when analyzed by age and occupation of the husband. The husband's smoking habits did not affect hi. wife'= risk of dying from other diseases, soon an stomach cancer, cervical cancer, and ischemic heart disease. The risk of developing emphysema and asthma seemed to be higher in nonsmoking wives of heavy smokers, but the effect was not statistically significant. The husbands t drinking habits seemed to have no effect on any cause of death in their wives, including lung cancer. Trichopoulos et al..' interviewed S1 women with lung cancer and 163 other hospital patients in Greece regarding their smoking habits and their husbands' smoking habits. Forty of the lung-cancer patients and 149 of the other patients were nonsmokers. Among the nonsmoking women, there was a statistically significant difference between the cancer patienta'-and the other patient. with respect To their husbands' amok ing habits . Estimates of relative r isk of lung cancer associated with having a husband who smokes were 2.4 for smokers of less than one pack per day and 3.4 for smokers of more than one pack per day. In two studies indicating a similar effect, it appears that chronic passive asking significantly increases the incidence of lung cancer. EFFECTS ON SPECIAL POPULATIONS The studies mentioned examined the effects of involuntary smoking on rela~ei~rely healthy population.. An exposure that is harmless for someone who is healthy may have a very different effect on sooson..~ Pith heart or lung disease or hypersensitivity to substances found in smoke. Effect. may differ in children, owing to their greater ventilation per unit of body weight. This section reviews the evidence on the effects of involuntary smoking on each of these special populations .

373 Cardiovascular Disease Carbon monoxide impairs oxygen transport in two ways. First, it competes with oxygen for hemoglobin binding sites. Second, it increases the affinity of oxygen for the remaining hemoglobin, thereby requiring ~ larger gradient in PO2 between the blood and tissue to deliver a given amount of oxygen. Carbon monoxide also binds to other heme-containing pigments, most notably ~yoglobin, for which it has an even greater affinity than for hemoglobin at low pot. The significance of this binding is unclear, but it nay be important in some tissues (such as heart muscled that have both high oxygen requirements and large amounts of Hemoglobin. In healthy people, the Comb content due to involuntary Baking is probably functionally insignif icant, with small changes demonstrable only under extreme exertion. In those with a limited cardiovascular reserve, however, any reduction in the oxygen~carrying capacity of the blood may be of greater importance. Ayres _ al. A ~~ exposed a group of patients to various concentrations of carbon monoxide (COHb, 99e ~ and found that they had lower arterial, mixed venous, and coronary sinus PO2 and decreased lactate extraction. Aronow and Isbell. and Anderson et al. ~ have shown a decrease in the mean duration of exercise before onset of pain in patients with angina pectoris exposed to carbon monoxide at low concentrations (50 and 100 ppm). Carboxyhemoglobin was significantly increased (2.91 after 50 ppm; 4. 5% after 100 ppm), and the systolic blood pressure, heart rate, and product of systolic blood pressure and heart rate (a measure of cardiac work) were all significantly lower at the onset of angina pectoris. In a continuation of this work, Aronow et al.5 ~ studied eight patients with angiographically demonstrated coronary arterial disease (~75% obstruction of at least one coronary artery} during two cardiac catheter izations . Dur ing the f irst, each patient smoked three cigarettes; during the second, each patient inhaled carton monoxide until the maximal coronary sinus COHb content equaled that produced by smoking during the first catheterization. Smoking increased the systolic and diastolic blood pressure, heart rate, left ventricular end-diastolic pressure (L1tEDP}, and coronary sinus, arterial, and venous COMb; no changes were noted in left ventricular contractility (dp/dt}, aortic systolic ejection period, or cardiac index; and there were decreases in stroke index and coronary sinus, arterial, and venous PO2. When carbon monoxide was inhaled, increased L=DP and coronary sinus, arterial, and venous COMb were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and there were decreases in left ventricular dp/dt, stroke index, cardiac index, and coronary minus, arterial, and venous PO2. These data suggest that carbon monoxide ha" a negative ionotropic effect on myocardial tissue, which results in the decreased dp/dt and stroke index. When the positive effect of nicotine on contractility and heart rate i" added by smoking, the net effect is increased cardiac work for the same cardiac output.

374 Aronow' also examined the effect of involuntary smoking on patients with angina pectoris. Ten patients (two smokers and eight nonsmokers ~ exercised af ter a control exposure to uncontaminated air, after exposure to 15 cigarettes smokes corer 2 n in a well-ventilated 3 0 . 8-m3 room, and af ter exposure to 15 cigarettes smoked over 2 h in an unventilated 30 . 8-m3 room. Carboxyhemoglobin rose f ram 1. 25% in the control situation to 1. 77% after exposure in the ventilated room, and to 2.28% after exposure in the unventilated room. The mean time of exercise until onset of angina decreased by 22% after exposure in the ventilated room and by 38% after exposure in eve unventilated row. The patients also had onset of angina at a lower heart rate and systolic blood pressure, and they had increases in heart rate and systolic and diastolic blood pressures. Aronow attributed thin to the possible absorption of nicotine {nicotine was not measured). The relatively low nicotine absorption documented under these conditions (see the previous section) makes it unlikely that nicotine would be responsible for these physiologic changes. Another possible explanation is that anxiety or aggravation associated with being in the smoke-filled room resulted in a stress response. The combination of increased blood pressure and pulse at the start of exercise and the increase in carboxyhemoglobin resulted in ~ greater decline in exercise time until angina for the measured carboxyhemoglobin than had been shown for carbon monoxide exposure alone. In summary, there in evidence that increases in carboxyhemoglobin capable of being produced by involuntary amok ing can reduce the exercise duration required to induce angina in some patients with coronary arterial disease. . . . Chronic Obstructive Lung Disease Patients with chronic lung disease constitute a second group who are limited in their ability to exercise and who might be particularly susceptible to involuntary smoking. Aronow et al. ~ had 10 patients with hypoxia chronic lung disease Spot < 70 tort ) exercise before and af ter a 1-h exposure to carbon monoxide at 100 ppm (COMb increased from 1.43% to 4.08%~. There was a significant reduction in mean exercise time until marked dyspnea, from 218.5 ~ to 146.6 s. There was no difference in exercise mean systolic or diastolic blOOd pressure, heart rate, product of systolic blood pressure and heart rate, or arterial PO2, pCO2, or pE before or after carbon monoxide exposure. The mechanism for this earlier induction of dyspnea remains unclear, because decreased oxygen transport to the exercising tissues should have been reflected in a shift to anaerobic metabolic and the development of acidosis. Persons with Allergies The existence of a true tobacco allergy remains unclear. There is no proof that specific sensitization to cigarette smoke occur.. s'

375 However, it is clear that allergic patients are more sensitive to a variety of environmental irritant-, including tobacco smoke. st The manifestations of this irritation may often mimic the allergic symptoms experienced by these patients when they come into contact with well-established allergens. It has also been demonstrated that cigarette-smoking by parents is a significant exacerbating factor in childhood asthma.3' Infants and Children Children have a higher incidence of acute respiratory illness than adults and may be more susceptible to air pollutant than adults, owing to their greater minute ventilation per unit of body weight. Several researchers have investigated the effects of parental smoking on the health of children. Colley~' found a relationship between parental smoking habits and the prevalence of respiratory illness in children. However, an even stronger relationship was found between cough and phlegm production in parents and respiratory infections in children. They postulated that the latter relationship resulted from the greater infectivity of these parents due to their cough and phlegm production. The relationship between parental cigarette-smaking and respiratory infection in their children would then occur because cigarette-smoking caused the parents to cough and produce phlegm and would not be indicative of a direct effect of smoke-filled air on the children. Bland et al. reported similar relationships. There have been several other research reports of associations between passive smoking in the home and symptoms or illnesses in children. I' 4' A telephone surveys' confirmed an earlier Survey,~5 in that children and adult nonsmokers subjected to household tobacco smoke had had a higher prevalence of acute respiratory illness in the preceding week than children and adult nonsmokers not so exposed. Reporting biases of the telephone respondents were not examined or controlled. Said and zalokar ~ ~ questioned Parisian high-school students {aged 9-19) about parental smoking and about their history of adenoidectomies and tonsillectomies. They found increases in the latter related to amount of tobacco smoked by either or both parents. This relationship was not always consistent (e.g., the% of such operations did not increase with increases in maternal smoking if paternal smoking was high). The prevalence of appendectomies was related to maternal smoking as well (and appendectomies were significantly correlated with the other operational Social status was not controlled; and the effect of actual {voluntary) smoking, a critical factor in this age group, 12 was not evaluated in this study, thereby limiting its usefulness. Harlap and Davies26 studied infant admissions to Hadassah hospital in West Jerusalem and found a relationship between admissions for bronchitis and pneumonia in the first year of life and maternal smoking habits during pregnancy. Data on postnatal maternal smoking habits were not obtained, but it can be assumed that most of the

376 mothers who smoked during pregnancy continued to smoke during the following year. A relationship between infant admission and maternal smoking habits was demonstrable only between the sixth and ninth months of infant life and was more pronounced during the winter month-. Mothers who smoke during pregnancy are known to have infants with a lower average birthweight than nonsmoking mothers. The relationship between maternal smoking and infant admission to the hospital found in this study was greater for low-birthweight infants, but the same relationship was found for normal-birthweight infant.. Harlap and Davies26 demonstrated a dose-response relationship between maternal smoking and infant admission for bronchitis and pneumonia; however, they also found a relationship between sternal smoking and infant admission for poisoning and injuries. This may indicate a bias in the study due to relationships that may exist between smoking and such f actors as parental neglect and socioeconomic class. In addition, hospital admission rates may not be an accurate index of infant morbidity. Colley et al. and Leeder et a1.~' studied the incidence of pneumonia and bronchitis in 2,205 children over the first 5 yr of life in relation to the smoking habits of both parents. They found that a relationship between parental Smoking habits and respiratory infection in children occurred only during the first year of life. They also showed a relationship between infant infection and parental cough and phlegm production that was independent of the effect of parental smoking habitat The relationship between parental smoking and infant infection was greater when both parents smoked and increased with the number of cigarettes smoked per day. The relationship persisted when social class and birthweight were Controlled for. Rantakallio3' 4° IS also found an increased incidence of pneumonia in children under the age of Be She studied 12,000 children born in northern Finland in 1966 and matched smoking mothers with nonsmoking mothers for various factors, including marital status, maternal age, and socioeconomic status. Children of smoking mothers had significantly higher morbidity {E' < 0.001) and were more likely to be hospitalized (~ ~ O.001}, and their hospitalizations were longer. Host of this excess morbidity was due to respiratory illness and was present in the first 5 yr of life, with the most pronounced effect occurring in the first year of life. CederllSf and Colleyt, stated that, When parents' respiratory sympto'as were taken into account, exposure of the child to cigarette awake generated by the parents' smoking had little if any effect upon the child's respiratory symptoms.. Lebowitz and Burrows32 and Schilling et a1.~' reported nonsignificant relationships between parental smoking and children's symptoms when parental symptoms were taken into account. They concluded that parents had a tibia-. toward reporting symptoms in their children when they themselves had such - Tager et al.57 58 examined the relationship of parental smoking habits and expiratory flow rates in children. They found a dose- dependent decline in the FEF t25-7St) in the children, with a greater decline occurring if both parents smoked than if one parent smoked, and

377 with the decline increasing with number of cigarettes smoked. This effect was independent of the smoking habits of the children. Pulmonary infection early in life has been shown to affect pulmonary function in children and adults adversely, and the decline in flow rates reported by Tager et al. may be secondary to the excess rink of pneumonia in infants whose parents smoke. They attempted to examine this by retrospectively asking the parents about childhood illness, but did not show an association between parental smoking and childhood infection, in contrast with the results of Rantakallio and Harlap. It is not clear whether this represents a true difference in the populations. In a further study of 5- to 9-yr-old children in the same population, Weiss et al. ~ reported that parental cigarette-smoking was linearly related to the occurrence of persistent wheeze (~ ~ 0.012) and lower degrees of mean forced midexpiratory flow. Current - persistent wheeze occurred in one of 57 children (1.8%) from households where both parents had never smoked; in 10 of 146 children (6 . 8% ~ with one parent currently smok ing; and in 20 of 169 children ( 12% ~ with both parents currently smoking. When the analysis was repeated with the exclusion of mothers with wheeze, the results were similar--O, 1.8, and 7 . 7% wheeze in children with no smoking parents, one smoking parent, and two smoking parents, respectively. Exclusion of fathers with wheeze gave O. 6.7, and 14% wheeze, respectively. In summary, children of smoking parents have an increased incidence of pers istent wheeze and may be at excess r isk of repiratory infection at least for the f irst year of life. They may also have reduced pulmonary function as adults. The exact interplay among the effects of maternal amok ing dur ing pregnancy, involuntary smok ing by children, and actual occurrence of infection has not been established. CONCLUSIONS · Tobacco smoke is a major source of pollution in the indoor envi ronment . · The nonsmoker absorbs measurable amounts of carbon monoxide and n icotine and may absorb small amounts of other constituents, owing to involuntary smok ing . · The amount of carbon monoxide absorbed owing to exposure to tobacco smoke in the environment varies from negligible amounts in well-ventilated office buildings to enough to raise carboxyhemoglobin contents by 2-3% in a 1- to 2-h exposure. · Ice carboxyhemoglobin produced by the mos t severe involuntary smoking exposures likely to occur in everyday living can reduce the maximal exercise capacity in normal, healthy adults, but does not e f feet submaximal exercise to any measurable degree. · Involuntary smok ing has not been shown to produce acute change in lung volumes, expi ratory f low rate., clog ing volume., or the slope of phase IT I of the single-breath nitrogen washout in normal, healthy adults; but long-term exposure to cigarette smoke is related to small-airway dysfunction and an increased incidence of lung cancer in healthy nonsmoking adults.

378 . - Small changes in visual and auditory vigilance have been demonstrated at carboxyhemoglobin contents capable of being produced by involuntary smoking. but no change in tents of complex function has been demonstrated. The interaction of fatigue, alcohol, and carbon monoxide exposure on complex functions, such as automobile driving, has not been investigated for COHb contents capable of being produced under normal conditions of involuntary smok ding . · Patients with angina pectoris have reduced exercise tolerance after involuntary smoking that may be a combination of psychologic stress and a reduction in oxygen delivery to the myocardium induced by carbon monoxide. Carbon monoxide clearly reduces the amount of exercise possible until the onset of angina in patients with angina pectoris at COMb contents that may be reached as a result of involuntary smoking. · Carbon monoxide has been shown in one study to reduce the amount of exercise that patients with hypoxia chronic obstructive lung disease can perform until the onset of dyspnea. · Most nonsmokers find it annoying to be exposed to cigarette smoke . Th is annoyance is probably due to substances in the gas phase of the smoke. · Ciga~ette-smoke exposure results in eye, nose, throat, and respiratory irritation. The eyes are most sensitive, followed by the nose and throat. The particulate phase of cigarette smoke seems to be predominantly responsible for this irritation. · Persons with allergies are more sensitive to the irritant effects of cigarette smoke. However, there is no proof of tobacco allergy. · Children whose parents smoke may be more likely to have respiratory symptoms, bronchitis, and pneumonia as infants and may have poorer pulmonary function as adults, compared with children of nonsmoking parents. This relationship is not independent of parental symptoms, socioeconomic class, and the smoking habits of the children; and it is associated with the number of cigarettes smoked per day by the parents. REFERENCES 1 . Anderson , E. W., R. J . Anderson , J . M. Strauch, N. J . Fortuin, and J. J. Knelson. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris. A study in ten patients with ischemic heart disease . Ann . Intern. Med. 79: 46-50, 1973. 2. Anderson, G., and T. Dalhamn. The risks to health of passive smoking . L~ikartidningen 70: 2833-2836, 1973 . 3. Aronow, W. S. }affects of passive smoking on angina pectoris. N. E:ngl . J . Med. 299: 21-24, 1978. 4. Aronow, W. S., and J. Cassidy. Effect of carbon monoxide on maximal treadmill exercise. A study in normal persons. Ann. Intern. Med. 8 3: 496-499, 1975. 5. Aronow, W. S., J. Cassidy, J. S. Vangrow, B. March, J. C. Kern, J. R. Goldsmith, M. Bohemia, J. Pagano, and M. Vawter. Effect of

379 cigarette Invoking and breathing carbon Monoxide on cardiovascular hemodynamics in angina1 patients. Circulation S0~2~:340-347, 1974. Aronow , W. S., J . Ferlinz , and F. Glauser . Ef feet of carbon monoxide on exercise performance in chronic obstructive pulmonary disease . Am. J. Med . 63: 904-908, 1977 . Aronow, W. S ., J . R. Goldsmith , J . C . Kern , and ~ . L . Johnson . Effects of smoking cigarettes on cardiovascular hemodynamics. Arch. Environ. Health 28: 330-332, 1974. 8. Aronow, W. S., and M. W. Isbell. Carbon monoxide effect on exercise-induced angina pectoris. Ann. Intern. Med. 79: 392-395, 1973. 9. Artho, A., and R. Roch. Caracterisation olfactive des composes de la fumee de cigarettes {Characterization of the olfactory properties of cigarette smoke components). Annales du Tabac (Section 1-11~:37-45, 1973. 10. Ayres, S. M., S. Giannelli, Jr., and M. Mueller. Myocardial and systemic responses to carboxyhemoglobin. Ann. N.Y. Acad. Sci. 174: 268-293, 1970. 11. Ayres, S . M., H. S. Mueller, J. J. Gregory, S. Giannelli, Jr ., and J. L. Penny. Systemic and myocardial hemodynam~c responses to relatively small concentrations of carboxyhemoglobin (COMB). Arch. Environ. Health 18:699-709, 1969. 1 2 . Banks , M . H ., B . R. Bewley , J . M ~ Bland , J . R. Dean , and V. Pollard. I,ong term study of smoking by secondary school-children. Arch. Dis. Child. 53 :12-19, 1978. 13. Barad, C. B. Smoking on the job: The controversy heats up. Occup. Health Saf . Jan-Feb . 19 79, p . 21 . 14. Bland, M., B. R. Bewley, V. Pollard, and M. H. Banks. Effects of children's and parent's smoking on respiratory symptoms. Arch. DiS. Childhood 51:100-105, 1978. 15. Cameron, P., J. S. Kostin, J. M. Saks, J. B. Wolfe, G. Tighe, B. Oselett, R. Stocker, and J. Winton. The health of smokers' and nonsmokers' children. J. Allergy 43:336-341, 1969. 16. Cameron, P., and D. Robertson. Effect of home environmental tobacco smoke on family health. J. Appl. Physiol. 57:142-147, 1973. 17. Cederlof, R., and J. Colley. Epidemiological investigations on environmental tobacco smoke. Scand. J. Respir. Din. (Suppl. 91~: 47-49, 1914. 18. Cole, P. V. Comparative effects of atmospheric pollution and cigarette smoking on carboxyhemoglobin levels in man. Nature 255:699-701, 1975. 19. Colley, J. R. T. Respiratory symptoms in children and parental smoking and phlegm production. Br. Med. J. 2:201-204, 1974. 2 0 . Colley , J . R. T ., W. W. Holland, and R. T . Corkhill . Influence of passive smoking and parental phlegm on pneumonia and bronchitis in early childhood. Lancet 2:1031-1034, 1974. 21. Dalton, T., M.-L. Edfors, and R. Relaunder . Mouth absorption of various compounds in cigarette smoke. Arch. Environ. Health 16:831-835, 1968. 22. Dalhamn, T., M.-L. Edfors, and R. Rylander. Retention of cigarette smoke components in human lungs. Arch. Environ. Health 17:746-748, 1968. .

380 23. Gliner, J. A., P. B. Raven, S. M. Borvath, B. L. Drinkwater, and J. C. Sutton. Monks physiologic response to long-term work during thermal pollutant stress. J. Appl. Physiol. 39:628-632, 1975. 24. Harke, B.-P. The problem of Impassive smoking.. MBnch. Hed. Wochenschr. 112:2328-2334, 1970. {in German; English summary) 25. Harke, H.-P., and A. Bleichert. On the problem of passive Making. Int. Arch. Arbeitamed. 29:312-322, 1972. (in German; English summery) 2 6 . Harlap, S ., and A. M. Davies . Infant admissions to hospital and maternal smoking . Lancet 1: S29-532, 1974. Hirayama, T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: A study from Japan. Br. Hed. J. 282:183-185, 1981. 2 8 . Hugod , C ., L. H . Bawk ins , and P. Astrup. Exposure of passive smokers to tobacco smoke constituents. Int. Arch. Occup. ~iron. Health 4 2: 21-29, 1978. 29. Johansson, C. R. Tobacco spoke in room sir--an experimental investigation of odour perception and irri~cating effects. Build. Services Eng . 43: 254-262, 1976. 30 . Johansson, C . R., and B. Ronge . Akuta irritationseffakter av tobaksr~k i ru~luft. (Acute irritation effects of tobacco smoke in the room atmosphere). Nord. Hyg. Tidskr. 46:45-SO, 1965. 31. Laties, v. G., and W. H. Merigan. Beha~riora1 effects of carbon monoxide on animals and man. Ann. R~. Pharmacol. Toxicol. 19: 357-392, 1979. 32. Lebowitz, M. D., and B. Burrows. Respiratory symptoms related to smoking habits of family adults. Chest 69:48-50, 1976. 3 3 . Leeder, S . R., R. Corkhill, L. M. Irwig, W. W. Holland, and J. R. T. Colley. Influence of family factors on the incidence of lower respiratory illness during the first year of life. Br. J. Prevent. Social Med. 30: 203-212, 1976. 3 4 . Luquette , A. ~ ., C . W. Landiss , and D. J . Merki . Some immediate effects of a smoking environment on children of elementary school age. J . School Health 40: 533-536, 1970. 35. National Clearinghouse for Smoking and Health. Adult Use of Tobacco, 1975. ACES. Department of Health, Education, and Welfare, National Clear inghouse for Smoking and Realth, June 1976 . 23 pp. 36. National Research Council, Committee on Medical and Biologic Ef feats of Environmental Pollutants . Carbon Monoxide . Washington, D.C.: National Academy of Sciences, 1977. 239 pp. 37. O'Connell, E. J., and G. B. Logan. Paren"1 smoking in childhood asthma. Ann. Allergy 32 :142-145, 1974. 38. Pin, P. E., F. Silverman, and R. J. Shephard. Physiological effects of acute passive exposure to cigarette smoke. Arch. Environ. Health 33: 201-213, 1978 . 39. Rantakallio, P. Relationship of maternal Smoking to morbidity and mortali~c~?~ of the child up to the age of five. Acta Paediatr. Scand. 67:621-~31, 1978. 40. Rantakallio, P. The effect of maternal smoking on birth weight and the subsequent health of the child. Early Human Dev . 2: 371-382, 1978 .

381 41. Raven , P. B ., B . L. Dr jerkwater , S . M. Horvath, R. O. Ruhling , J. A. Gliner, J. C . Sutton, and N. W. Bolduan. Age, smoking habits, heat stress, and their interactive effects with carbon monoxide and peroxyacetyluitrate on man's aerobic power. Int. J. Biometeorol. 18: 222-232, 1974. 4 2 . Repace , J . L ., and A. H . Low rey . Indoor air pollution , tobacco smoke, and public heal~ch. Science 208: 464-472, 1980. 4 3 . Rumnel , R. M., M. Crawford , and P. Bruce . The physiological ef feats of inhaling exhaled cigarette smoke in relation to attitude of the nonsmoker . J. School Health 45: 524-529, 1975. 44. Russell, M. A. H., P. V. Cole, and E. Brown. Absorption by non-smokers of carbon monoxide from room air polluted by tobacco smoke . Lancet 1: 576-579, 1973. 45. Russell, M. A. H., and C. Feyerabend. Blood and urinary nicotine in non-smokers. Lance t 1 :179-181, 1975. 4 6. Rylander , R., Ed . Environmental Tobacco Smoke Ef fects on the Nonsmoker. Report from a WorkShop. Scand. J. Respir. Dis. (Suppl. 91) :1-9G, 1974. 47. Rylander, R. Perspectives on environmental tobacco smoke effects. Scand. J. Respir. Dis. (Suppl. 91) :79-87, 1974. 4 8. Said, G., and J. Zalokar . Incidence of upper respiratory tract disorders in children of smokers. Ann. d'Oto-laryogol. Chir. Cer~rico~Fac . 95: 236-240, 1978. 49. Schilling, R. S. F., A. D. Letai, S. L. Hut, G. J. Beck, J. B. Schoenberg, and A. Bouhuys. Lung f unction, respiratory d isease, and Smoking in families. Am. J. Epidemiol. 106: 274-283, 1977. 50. Seppanen, A. Smoking in closed space and its effect on carboxyhae~lobin saturation of smoking and nonsmoking subjects. Ann. Clin. Res. 9: 281-283, 1977. 51. Seppanen, A., and A. J. Uusitalo.. Carboxyhaemoglobin saturation in relation to smok ing and var ious occupational conditions . Ann . Clin . Res. 9: 261-268, 1977. 52. Shepharo, B. J., R. Collins, and F. Silverman. Responses of exercising subjects to acute passive ~ cigarette smoke exposure . Environ. Res. 19: 219-291, 1979. 53. Steer, F. Tobacco and the nonsmoker. A study of subjective symptoms . Arch. Environ. Health 16: 443-446, 1968. 54 . Srch, M. Uber die Bedeutung des Kohlenoxyds beim Zigarettenrauchen im Personenkraftwageninneren. Dtsch. Z. Gesamte Gerichtl. Mede 60~37:80-89, 1967. (in German) 55. Sterling, T. D., and D. H. Kobayashi. Exposure to pollutants in enclosed Living spaces. ~ Environ. Res. 13:1-35, 1977. 56. Szacikowski, D., H.-P. Marke, and J. Angerer. Body burden of carbon nonoxide from passive smoking in offices. Innere Med. 3:310-313, 1976. 5 7. Tager , I. B., B. RoSner , P. V. Tishler, F. E. Speizer , and E. H. Kass. Household aggregation of pulmonary function and chronic bronchitis. Am. Rev. Respir. Dis. 114 :485-492, 1976. 58. Tager, I. B., S. T. Weiss, B. Roster, and F. E. Speizer. Effect of parental cigarette smoking on the pulmonary function of children. Am. J. Epidemiol. 110 :15-26, 1979.

382 59. Taylor, G. Tobacco smoke allergy--Does it exist? Scand. J. Respir. Dis. (Suppl. 91) :50-55, 1974. 6 0 . Trichopoulos , D., A. Ralandidi , L. Sparros , and B. MacMahon . Lung cancer and passive Stoking . Int. J . Cancer 27 :1-4, 1981. 61. U.S. Department of Health, Education, and Welfare, Public Health Service. Smoking and Health. A Report of the Surgeon General. DREW Publication No. (PHS) 79-50066. Washington, D.C.: U.S. Government Printing Office, 1979. [1250] pp. 6 2 . ~ . S. Department of Transportation, Federal Aviation Administration, and U.S. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health. Report on Health Aspects of Smoking in Transport Aircraft. Washington, I).C.: U.S. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health, Division of Technical Services, 1971. 85 pp. Waite, C. L. Letter to the editor . N. Engl. J. Hed. 299: 897, 1978. Wakeham, H . R. R. Environmental carbon monoxide f rom cigarette smokinq--A critique. Prev. Med. 6:S26-534, 1977. 65 . Weber, A., T. Fischer, and E. Grand dean. Passive smoking: Irritating effects of the total smoke and the gas phase. Int. Arch. Occup. Environ. Health 43 :183-193, 1979. 6 6 . Weber , A., C. Jermini , and E. Grandjean. Irritating effects on man of air pollution due to cigarette smoke. Am. J. Public Health 6 6 : 672-676, 1976 . 6 7 . Weiss , S . T., T . B. Tager , F. E. Speizer , and B. Roaner . Persistent wheeze. Its relation to respiratory illness, cigarette smoking, and level of pulmonary function in a population sample of children. Am. Rev . Respir . Dis. 122: 697-707, 1980. 6 8. White, J . R., and H. F. Froeb. Sn~all-airways dysfunction in non='aoker~ chronically exposed to tobacco smoke. N. Engl. J. Med. -302: 720-723, 1980. 6 9 . Yabrof f, ~ ., E . Meyers , fir. Fend , N. David , M. Robertson , R. Wr ight , and R. Braun. The role of atmospheric carbon monoxide in vehicle accidents. Menlo Park, Cal.: Stanford Research Institute, February 1974. INDOOR AIRBORNE CONTAGION . . Among the pollutants of indoor air are biologic aerosols produced by people when they cough, sneeze, ~sing, spit, blow their noses, or even talk. Discussion of airborne infection is as old as recorded history, but refined concepts of contagion, expressible in quantitative terms, are surprisingly recent. Less then 50 yr ago, William F. wells synthesized a coherent theory that has now been tested and amplified. Even though the ideas are not yet imbedded in medical thinking and teaching, they pertain to a very important medical and public-health problem. Airborne contagion is the mechanism of transmission of most acute respiratory infections, and these are the greatest of all causes of morbidity. Primary pulmonary tuberculosis is also transmitted In this way. Airborne contagion from person to person is mostly an indoor phenomenon.

383 ASSESSING INDOOR BIOGE1NIC POLLUTANTS In approaching biogenic pollutants, the dearth of data on indoor prevalence and the lack of satisfactory study methods constitute a single complex problem. Although most indoor biologic agents are distinctive microscopically, many categories of biogenic particles are ~not. For those which also fail to grow recognizably in culture, no practical enumeration is yet possible. The penetration of biologic particles into buildings has been little studied, but seems to depend most on the extent of mass flow through windows and doors . Additional factors in ventilation ~ ~ ~ ~ include incident-wind speed and direction, negative pressurization by exhaust fans, and stack effects (which may be minor in warm periodic. Air leaks between structural members ~ Trackage ~ foster ventilation; window and door frames contribute less. 'I Tracer gases often have suggested br isk inf titration of air into structures; however, the capacity of windborne particles to negotiate minute cracks, certainly less, remains to be estimated. Sampling for biologic agents both indoors and outdoors Is fundamental to studies of their sources. Furthermore, because particles may remain indoors for a long time after infiltration from free air, analyses of indoor-outdoor relationships must be sensitive to the resulting lag effects. 'I Biogenic pollutants bear complex and varied organic structures, which defy automated chemical assay. Culture or direct microscopic enumeration offers ~ workable, although tedious, alternative for some particles; for others, i~maunofluorescence and multiphasic microscopy have demonstrated potential. Concentrations of airborne biogenic dusts that lack morphologically defined unit-e might be estimated by subjecting extracts of bulk aerometric sample" to immunoassay; methods suitable for amorphous components of house dust have been discussed elsewhere. ~ ~ Because many biologic pollutants are relatively large aerodynamically, whereas others are quite small or undefined, precautions to minimize size-related collection bias are essential. Rates of circulation indoors are generally lower and often more nearly constant than those outdoors. However, the velocities generated by fans, human activity, and pronounced convection are important; they readily bias recoveries based on fallout and may affect collection with station traps. " As a result, differences in particle recovery between indoor and outdoor sites may reflect prevailing flow conditions more than real transmural differences in aerosol prevalence. Despite their longstanding popularity, ~gravitational. methods involve particularly marked, -~ize-related bias in collections. ·2 And the small samples obtained and the lack of volumentric capability further limit the usefulness of data obtained in this way. Suction devices have been used sucessfully for indoor studies, and miniature impactors are adaptable for this purpose. In all applications, the s iting of samplers ~ris-a-vis probable pollutant sources should be considered and points of low flow avoided. In contrast with chemically simpler pollutants, biogenic agents exhibit limited direct toxicity, more often provoking infection.

384 Airborne transmission of infectious agents is facilitated indoors by the prompt dispersion of particle. In general, indoor bacteria appear to have indoor sources; date on outdoor airborne bacteria are severely limited. One study has reported bacteria in outdoor air at up to 4,000/m . ~ Another study presented indoor-to~outdoor ratios of O. . 76-14 . 2S, ~ ~ witch much site-to~Site variation. Outdoor concentrations may depend on high wind velocity and temperature, and are apparently highest in seer. ~ ~ ~ Bacteria from outdoors do contaminate interiors, but to an unknown decree. Clostridium Perfrinaens, primarily a soil bacterium, has been found in room air and house dust.7' The primary source of bacteria in most indoor places is the human body. s' Although the major source is the respiratory tract, S2 67 there are other sources. According to Clark and Cox, i. 7 million skin scales are shed per minute per person, with an average of four viable bacteria per scale. Abrasion in the priory factor in the rate of losses 56 and showering increases the rate of loss of bacteria. ~ ~ " " EVIDENCE OF INDOOR AIRBORNE INFECTION Droplet nuclei are the dried residues of the smallest respiratory droplets. They range in size from 1 to 3 - , disperse rapidly throughout the air of a room, and are carried wherever the air goes. Settling velocity is ~.;v...~gligible in comparison. with the velocity of air movement in occupied proms. The concentric of viable organism attached to droplet nuclei may be reduced by .~aPtural die-away, air filtration, or exchange with outdoor air. Standard filter. used in ventilating systems remove a small f Faction . There in no reservoir of infectious droplet nuclei other than the respiratory tracts of people carrying the organisms. Welled believed that aerial transmission from per son to person occurs indoors where droplet nuclei are in of f icient concentration to be a hazard . Infectious contact ~ contagion ~ require" proximity in time and space between host and victim, but can be extended to the confines of the enclosed atmosphere and to a shared ventilating system if the air within the system i8 recirculated 68 the recirculating system then becomes a condemn enclosed atmosphere. Tuberculosis In the 1950s, a study was carried out at the Veterans' Administration Hospital in Baltimore in which guinea pigs breathed air vented from a tuberculosis; ward. Tubercle bacilli from the patients, which had gone through the ventilating dusts and through the upper respiratory tracts of the guinea pigs, were positively identified in the lungs of infected animals. " On the basis of this and other evidence, it is generally agreed that the initial infection of the lungs with tuberculosis is airborne.

385 Measles An early demonstration of airborne infection involved the indirect approach--the control of epidemic spread by disinfecting the air. The study was carried out in the 1940s in schools in Germantown and Swarthmore, Pennsylvania. by Wells et al. t2 Shortly after ultraviolet {W) air~disinfection fixtures had been installed in the test schools, a major measles epidemic struck. In both communities, the nonirradiated schools had sharp outbreaks of measles, and the W-irradiated schools did not. The reduced spread of infection in the irradiated schools could be attributed to the single factor that was different, namely, the concentration of viable airborne measles virus. During the spring of 1974, a sharp outbreak of measles occurred in an elementary school near Rochester, New York. I' Measles was introduced into the school by a girl in the second grade. Twenty-eight secondary cares followed after an incubation period of about 10 d; these were distributed among 14 classrooms served by the same ventilating system. The wide distribution of the 28 secondary cases among children who had never even occupied the same room as the child with the index case and the fact that about 709 of the air was recirculated, and hence shared by all children served by the ventilating system, led to the conclusion that measles reached the war ious classrooms via the ventilating system. Asian Influenza - Dur~ng the 1957-1958 pandemic of Asian influenza, the main building of the veterans' Mospital in Livermore, California, had W air disinfection installed throughout, and the patients in the building constituted a test group. 57 ~-~--~- ~~ ~~--~ :___~_~AA ravens An no: ~yllwL Ann new L ClU~CI1~:~ buildings served an controls. No mixing of test and control groups was allowed. Hospital personnel and visitors who mingled in the outside community were relied on to introduce infection into the two patient populations. The incidence of serologically diagnosed influenza ^~nq the 209 patients living in the W-~rradiated building was 21; among the 396 patients living in nonirradiated buildings, it was 19%. Like the measles study, this demonstration provided evidence consistent with transmission of the infectious virus by air. Schulman demonstrated that natural transmission of influenza from mouse to mouse is airborne,'. and the studies of various viral infections by Knight and collaborators are compatible with aerial transmission in humans. 4' Smallpox In 1970, in a West German hospital, a patient with smallpox infected 19 other persons, despite rigid isolation procedures. Investigators from the World Health Organization and West Germany demonstrated that smallpox, like influenza, could be transmitted by air

386 currents, but smallpox has been eradicated and need not be considered f urther . ~ 3 These selected epidemiologic studies show the kind of evidence supporting the droplet-nucleus concept of indoor airborne contagion. There have, of course, been many other studies, including unsuccessf ul attempts at con f irmation of some of those mentioned. In retrospect, the failures appear to be attributable to inadequacies of experimental design. The droplet-nucleus mechanism of Wells is emerging as the successor, for most respiratory infections, to the direct-contact mechanism of Chapin. Other Types of Airborne Infection Infections in hospitals have not been shown to be pr imarily airborne, and such organisms as staphylococci, streptoccci, and gram-negative bacilli are not characteristically transmitted by air. Nevertheless, hospital-acquired infections of the lower respiratory tract are presumptively airborne, inasmuch as inspired air is the most likely vehicle for carrying organisms to the lungs. Hospital patients are often hypersusceptible to infection, and transmission may occur in ways not often seen in the general population. A major epidemic of Legionnaire's disease occurred in a hospital into which outside air contaminated with Leqionella E~neumophila leaked during adjacent construction. " This organism is unusual among bacterial pathogens, in that it apparently exists in outdoor natural reservoirs (soils ~ and infection is possible through inhalation of contaminated outdoor air. ~ ' ~ ~ The most common mode of spread of Legionnaire ' s disease involves air-cooling equipment that becomes con~caminated and produces concentrated bacterial aerosols. ~. 3' s. Air-conditioning and -humidifying equipment can be a source of intramural bacterial aerosols. Cool-mist vaporizers and nebulizers that can produce heavily contaminated aerosols are of special co tern ~ ~ ~e ~' 23 .0 .... S2 63 77 8~ Apparently, bacterial contamination of such units approaches 1009~- 2 0 7t Pseudomonas appears to be the most commonly isolated bacterial genus. 1 ~ 23 ~ O `. ~ 3 Smith' ~ reported several cases of Acinetobacter infection resulting from contaminated cool-mist vaporizers. Evaporative humidifiers, although often contaminated with bacteria, are less likely to produce bacteria-laden aerosols, ~ ' ~' Disinfection of any humidifying unit is effective only temporarily,' ~' .° and Rosenzweig'~ has recommended banning cool-mist l,umid~f iers for home or hospital use . Other appliance. reported to be potential sources of indoor bacterial aerosols are flush toilets. 22 Ice machines are also potential foci for bacterial contamination. s Rylander et al. ' 3 discussed carpeting as a focus for bacterial contamination, but concluded that carpeting can, in fact, reduce airborne bacterial concentrations by trapping bacteria-laden particles in the pile. There are specific sites at which bacteria may become airborne at high concentrations. Factories that process organic materials may contain dense bacterial aerosols.~3 .~ 5~ 6~ t.

387 In some interior situations, even low bacterial concentrations are of concern. A submarine constitutes a closed system in which buman-source bacteria could accumulate to an undesirable extent. Morris and FallonSt 6° and Wright et al. discussed this subject and concluded that modern air-cleaning in submarines creates an environment unusually low in bacteria. Also of concern are bacterial concentrations and patterns of bacterial distribution in aircraft, especially those used to transport infectious patients. Clayton et alps reported that, whereas in the Boeing 707 artificially aerosolized indicator bacteria are con fined to the rear portions of the aircraft, in the C130E Hercules such bacteria become rapidly disseminated throughout the vehicle. Bacteria (both surface and airborne) in the hospital environment warrant attention. Bacterial content in a hospital environment depends primarily on the presence of humans and on the degree and types of their activity.s '. .. S2 62 74 Bacterial products may contaminate indoor air in the absence of bacterial cells. Fine dust in a detergent factory was found to contain Bacillus subtil~s enzymes.3S Workers became ill when exposed to .- sewage-sludge dust; the active factor was presumed to be airborne endotoxin.Ss Finally, laboratory illness has occurred as the result of inhalation of tuberculin aerosols during operation of a high-speed centrifuge. Several fungi--BlastomYces, Cryptococcus, Coccidioides, and Histoplasma, all known primarily as human pathogens--ex~st in natural reservoirs, usually associated with bird or animal emanations. 2 ~ 2 ~ 47 S. 85 The extent of contamination of interior situations by these fungi is unknown. However, all are known to enter the body by the respiratory route,2 2t 2S 26 32 35 IS and Coccidioides and Histoplasma are known to be highly infective.6S Thus, natural reservoirs near human habitation will surely result in some interior contamination leading to a possible risk of infection 2 ~ -l ~ O ~ 3 ~ 2 ~ S For example, 5 x 107 viable Cryptococcus spores have been found per gram of dry pigeon fecal material,2 and the spores were present in more than half the pigeon droppings examined ~ 5--droppings that are often abundant in areas of dense human populat ion . Candida albicans and dermatophytes have been recovered from air and dust samples in clinic rooms especially during and after examination of infected patients e ~. ', .. 75 However, Friedrich38 reported only 3% of air samples and 14% of dust samples positive in examining rooms dur ing per iods with no patients . IMPORTANCE OF AIRBORNE CONTAGION , In a 9.5-yr study of 85 families in Cleveland/ Ohiol Dingle found that 63% of all illnesses were respiratory. 24 According to the National Health Survey, respiratory conditions (predominantly upper respiratory disease and ~influenza.) account for more than half of all acute condition", including illnesses and injuries. The incidence

388 of respiratory conditions is just under one per person per year, and, on an average, each person's activity is restricted for 4.5 d. If one grants that the respiratory conditions referred to are mostly in the category of indoor airborne contagion, the problem is seen to be enormous. Loss of time from work or from school exceeds that from any other cause. PREVENTION OF I~R AIMS CO="ION Less-crowded living conditions, isolation, and vaccination have helped to reduce airborne contagion. We consider here a measure that, although neglected in the past, is assuming increasing importance: air dis infection in buildings . Control of epidemic spread of airborne contagion requires that each infectious case beget, on the average, no more than one new case. The concentration of infectious droplet nuclei must be reduced to the point where susceptible people stand but a s~11 chance of inhaling an infectious particle. In relatively airtight buildings where the capacity of the ventilating system, the fraction of fresh-air wakeup, and the efficiency of the filters are known, where the number of infections in each generation of an epidemic is available from records, and where the pulmonary ventilation and duration of exposure of the occupant" can be estimated, the essential characteristics of airborne contagion can be dealt with quantitatively. In the 1974 measles epidemic in a school near Rochester, New York, this was done. " During the first generation, the number of infectious particles (quanta of infection) produced per minute in the index case was 93 -an amount that produced a concentration in recirculated air of 1 per 5.17 m3. Twenty-six susceptible children breathing this sparsely infected air acquired measles and appeared as cases in the second generation. Such calculations provide architects and engineers with an appreciation of the particulate nature and the quantitive aspects of a characteristic airborne infection. Thus, the routes of transmission are airborne through infiltration and ventilation, from person to person, and via fomites. The effects of ventilation rates are unknown.' 53 There are interaction. between microorganisms and pollutants, ss between indoor combustion and smoking, in producing respiratory illness, especially in children and the infirm.~' 76 REFER~K:ES ~- 1. Airoldi, T.' and W. Litaky. Factors contributing to the microbial contamination of Goldwater humidified. Am. 3. Med. Technol. 38: 491-495, 1972. 2. Ajello, L. Comparative ecology of respiratory mycotic disease agents . Bacterial . Rev. 31: 6-24, 1967. 3 . Ajello, L., R. Maddy, G . Crecelius, P. G. Bugenholtz , and L. B. Hall. Recovery of C`xcidioides immitis from the air. Sabouraudia 4 :92-95, June, 1965.

389 c i, - 4. Bamert, P., and F. Roth. Bacterial traneeission caused by air humidifiers. Schweiz. Med. Wbehenschr. 104~50~:1856-1859, 1974. {in German; English summary) Blevins, A., D. Armstrong, T. E. Riehn, and L. Borch. The coordinating role of the microbiologist in hospital epidemiology. (Abstract) Abstracts of the Annual Meeting Am. Sac. Microblol. 79:316, 1979. 6. Botard, R. W., and D. C. Relley. A survey to determine the occurrence of Histoplanma capsulatum and Cryptococcus neofor~ns in a tr-conditioners . Mycopathol . lIycol . Appl . 37 {4 ): 372-376, 1969 . 7. Bovallius, A., B. Bucht, R. Roffey, and P. ~ Be. Three-year investigation of the natural airborne bacterial flora at four localities in Sweden. Appl. Environ. Microbial. 35(S):847-852, May, 1978. 8. Buhles, W.C., Jr. Airborne staphylococcic contamination in experimental procedures on laboratory animals. Lab. Anim. Care 19:465-469, 1969. 9. Burge, H. A., W. R. Solomon, and J. R. Boise. Hicrobis1 prevalence in domestic humidifiers. Appl. Environ. Microbiol. 39~41:840-844, 1980. 10. Cartwright, R. Y., and P. R. Hargrave. Pseudomonas in ventilators. Lancet 1:40, 1970. 11. Case, S. K., S. P. Almeida, W. J. Dallas, J. M. Fournier, R. Pritz, J. Cairns Jr., K. L. Dickson, and P. A. Pryfogle. Coherent microscopy and matched spatial filtering for real-time recognition of diatom species. Environ. Sci. Technol. 12:940-946, 1978. 12. Chatigny, M. A., and R. L. Dimmick. Transport of aerosols in the intramural environment, pp. 95-110. In R. L. Edmonds, Ed. Aerobiology. The Ecological System. Approach. Stroud~burg, Pa.: Dowden, Hutchinson and Russ, Inc., 1979. 13. Cinkotai, F. F., M. "G. Lockwood, and R. Rylander. Airborne micro-organisms and prevalence of bys~inotic symptoms in cotton mills. Am. Ind. Byg. Assoc. J. 38:554-559, 1977. 14. Clark, R. P., and.R. N. Cox. The generation of aerosols from the human body, pp. 413-426. In J. F. P. Bers and R. C. Winkler, Eda. Airborne Transmission and Airborne Infection. New York: John Wiley & Sons, Inc., 1973. 15. Clayton, A. J., D. C. O'Connell, R. A. Gaunt, and R. E. Clarke. Study of the microbiological environment within long- and medium-range Canadian forces aircraft. Aviat. Space Environ. Med. 47: 471-482, 1976 . 16. Clayton, Y. M., and G. Midgley. Estimation of dermatophytes (ringworm fungi) and Candida spores in the environment. J. Med. Microbiol. 4~2~:Piii-Piv, 1971. (abstract) -~i. 17. Cleton, F. J., Y. S. van der Mark, and M. J. van Toorn. Effect of shower-bathing on dispersal of recently acquired transient skin flora. Lancet 1:865, 1968. 18. Cordes, L. G., D. W. Fraser, P. Skaliy, C. A. Perlino, W. R. Elsea, G. F. Mallison, and P. S. Hayes. Legionnaires' disease outbreak at an Atlanta, Georgia, country club: Evidence for spread from an evaporative condenser. Am. J. Epidemiol. 111:425-431, 1980.

390 19. Covelli, B. I)., J. Xleeman, JO E. Martin, W. L. Landau, and R. r`. Hughes. Bacterial emission from both vapor and aerosol humidifiers. Am. Rev. Respir. Dis. 108: 698-701, 1973. 20. Crowley, T. P. Contaminated humidif iers. J. Am. Hed. A=soc . 240: 348, 1978. 21. D'Alessio, D. J., R. H. Heeren, S. L. Hendricks, P. Ogilvie, and M. L. Furcolow. A starling roost as the source of urban epidemic histoplasmosis in an area of low incidence. Am. Rev. Respir. Dis. 92: 725-731, 1965. 22. Darlow, H. M., and W. R. Bale. Infective hazards of water-closets. Lancet 1 :1196-1200, 1959. 23. Dickgiesser, N. Examinations about the behavior of grampositive and gramnegative bacteria in dry and moist atmosphere. Zentralbl. Bakteriol. ParasitenJcd. Infektionskr. Hyg. Abt. 1 Orig. Reihe B 167:48-62, 1978. (in German; English abstract) 2 4. Dingle, J. H. An epidemiolog ical study of illness in families. Harvey Lectures S3 :1-24, 1957. Doto, I . L., F. E. Tosh, S. . F. Farnsworth, and M. L. Furcolow. Coccidioidin, histoplasmin, and tuberculin sensitivity among school children in Maricopa County, Arizona. Am. J. Epidemiol. 95:464-474, 1972. 2 6. Orutz, D. J. Urban coccidioidomycosis and hi~toplasmosis . N. Engl. J. Hed. 301: 381-382, 1979. 27. Dutkiewicz, J. Exposure to dust-borne bacteria in agriculture. I. Environmental studies. Arch. Environ. Bealth 33: 250-259, 1978. 28. Dutkiewicz, J. Exposure to dust-borne bacteria in agriculture. II. Immunological survey. Arch. Environ. Health 33 :260-270, 1978. 29. Dutkiewicz, J., and A. Molooznik. Correlation between dust concentration and microorganism count in the air of grain mills and grain silos. Arch. Byg. 8akteriol. 154 :371-377, 1970. (in German; English summary) 30. Eckmann, B. B., G. L. Schaefer , and M. Huppert. Bedside interhuman transmission of coccidioidomycosis via growth on fomites. An epidemic involving six persons. An. Rev. Respir. Dis. 89 :175-185, 1964 . 31. Eickhoff, T. C. Epidemiology of Legionnaires ' disease. Ann. Intern. Med. 90: 499-502, 1979. 32. Canons, C. W. The natural occurrence of pathogenic fungi, pp. 22-30. In E. W. Chick, A. Balows, and M. L. Furcolow, Eds. Opportunistic Fungal Infections. Proceedings of the Second International Conference. Springfield, Ill.: Charles C Thomas, Publisher, :~.975. 33. Fass, R. J., and S. Saslaw. Earth Day histoplasmosis. A new type of urban pollution. Arch. Intern. Hed. 128: 588-590, 1971. 34. Fitzgerald, R. H.-, Jr. Microbiologic environment of the conventional operating room. Arch. Surg . 114: 772-775, 1979 . 3S. Flindt, M. L. B. Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. L^ncet 1: 1177-1181, 1969. 3 6 . Flynn , N. M., P. D. Boepr ich, M. M. Kawachi , K. R . Lee , R. M. Lawrence, E . Goldste in, G. W. Jordan, R. S . Kundarg i, and G. A.

391 Wang. An unusual outbreak of windborne coccidioldomycosis. N. Engl. J . Med. 301: 358-361, 1979 . 37. Fraser, D. W., D. C. Deubner, D. L. Hill, and D. R. Gilliam. Nonpneumonic, short-incubation-period legionellosis (Pontiac fever in men who cleaned a steam turbine condenser. Science 205:690-691, 1979. 3 8 . Fr iedr ich , E ., and R. Blaschke-Helimessen. Candida in the rooms of a dermatological clinical center. Rosen 18:97-105, 1975. fin German; English summary) 39. Gip, L. Investigation of the Occurrence of Dermatophyte" on the Floor and in the Air of Indoor Environments. Acts Derm. Venereal. (Stockholm) 46 (Suppl. 58) :1-54, 1966. 40. Grieble, H. G., F. R. Colton, T. J. Bird, A. Toigo, and L. G. Griffith. Fine-particle humidifiers. Source of Pseudomonas aeruginosa infections in a respiratory-disease unit. N. Engl. J. Med. 282:531-535, 1970. 41. Grunnet, K., and J. C. Hansen. Risk of infection from heavily contaminated air. Scand. J. Work Environ. Health 4~4~: 336-338, 1978. Basenclever, H. F. Impact of airborne pathogens in outdoor systems: histoplasmosis, pp. 199-208. In R. L. Expands, Ed. Aerobiology: The Ecological Systems Approach. Stroudaburg, Pa.: Dowden, Hutchinson and Pass, Inc., 1979 . Henderson, D. A. The eradication of smallpox. Sci . Am. 235 (4~:25-33, 1976. 4 4 . Hodges, G. R., J. N. Fink , and D. P. Schlueter. Hypersensitivity pneumonitis caused by a contaminated coolest vaporizer. Ann. Intern. Med. 80: 501-504, 1974. 45. Rojovec, J., and A. Fiser. The microflora of the atmosphere in chicken houses for broilers. Dtsch. Tierarztl. Wochenschr. 75: 483-486, 1968 . ~ in German; English summary ~ Jopke, W. H., and D. R. Mass . Contamination of dishwashing facilities. Hospitals 44~6~:124-127, March 16, 1970. Khan , Z . U., M. Pal , ~ . S . Randhawa, and R. S . Sandhu. Carriage of cr~rPtococcus neoforoasns in the crops of pigeons. J. Med. Microbial. 11: 215-218, 1978 . 4 8 . Klein, H.-J., and M. Runze. Experimental investigations on the spread of Pseudomonas aeruginosa by a cold aerosol apparatus for moistening of the room atmosphere. Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg. Abt. 1 Orig. 216~2) :199-209, 1971. (in German; Engish abstract) 49. Knight, V. Airborne transmission and pulmonary deposition of respiratory viruses, pp. 1-9. In V. Knight, Ed. Viral and Mycopla~mal Infections of the Respiratory Tract. Philadelphia: Lea and Febiger, 1973. 50. K5sters, J., and W. Huller. Exposure of personnel to bacteria in mass poultry husbandry. Zentralbl. Veterinarmed. Reihe B 17:154-158, 1970. {in German; English summary) 51. Lacey, J. Microorganism" in air of cotton mills. Lancet 2:455-456, 1977. 52. Leedom, J. M., and C. G. Loosli. Airborne pathogens in the indoor environment with special reference to nosocomial (hospital}

392 infections, pp. 208-237. In R. L. at, As- "robiol~. The Ecological Systems Approach. Stroudeburg, Pa.: Dowden, Butchinson and Ross, Inc., 1979. 5 3 . Lewis , ~ . E ., A. R. Foster , ~ . J. Mullen , R. N . Cox , and R. P . Clark. Aerodynamics of the Herman microenvironment. I.ancet 1: 1273-1277, 1969. 54. Mantovani, A. The role of animals in the epidemiology of the r~,coses . Mycopathologia 65: 61-66, 1978 . 55. Mattsby, I., and R. Rylander. Clinical and immunological findings in workers exposed to sewage dust. J. Occup. Med. 20:690-692, 1;978. 56. May, K. R., and N. P. Pomeroy. Bacterial dispersion frown the body surface, pp. 426-432. In J. F. Bers and R. C. Winkler, Eds. Airborne Transmission and Airborne Infection. New York: John Wiley and Sons, Inc., 1973. 57. McLean, R. L. The effect of ultraviolet radiation upon the transmission of epidemic influenza in long-term hospital patients. Am. Rev. Respir. Dis. (Suppl. 83) :36, 1961. 58. McNall, P. E., Jr. Practical methods of reducing airborne contaminants in interior spaces. Arch. Environ. Health 30 :S52-556, 1975. 59. Morr is, J. E. W. Microbiology of the submarine environment. Proc. R. Soc. fled. 65:799-800, 1972. 60. Morris, J. E. W., and R. J. Fallon. S&cudies on the microbial flora in the air of submarines and the nesopharyngeal flora of the crew. J. Byg . 71: 761-770, 1973. 61. Mundt , J. O., E. J. Anandam, and ~ . E. McCarty. Streptococceae in the atmosphere of plants processing vegetables for freezing. Health Lab. Sci. 3 :207-213, 1966. 62. Nelson, C. L. Er'-..;~ronmental bacteriology in the unidirectional (horizontal) operating room. Arch. Surg. 114 :778-782, 1979. 63. Pennington, J. B., J. I`umley, and F. O'Grady. The growth of Pseudomonas pyocyanea in Gerthur condenser humidifiers. An experimental study. Anaesthesia 21: 211-215, 1966. 64. Peterson, J. E. Estimating air filtration into houses: An analytical approach. ASEIRAE J. 21~1~:60-63, 1979. 65. Pike, R. M. Iaboratory-~sociated infections: Incidence, fatalities, causes, and prevention Ann. Rev. Microbiol. 33:41-66, 1979. 66. Radonic, M. Systemic allergic reactions due to occupational inhalation of tuberculin aerosols. Ind. Med. Surg. 35:24-26, 1966. 6 7 . Resnikov, H., J. B. Leggo, and D. J. Dawson . Investigation by seroagglutination of strains of the MYcobacterium intracellulare- M. scrofulaceum group from house dusts and sputum in southeastern Queensland. Am. Rev. Respir . Dis. 104: 951-953, 1971. 68. Riley, E. C., G. Murphy, and R. L. Riley. Airborne spread of measles in a suburban elementary school. Am. J. Epidemiol. 107: 421-432, 1978. 69. Riley, R. L., C. C. Hills, F. O'Grady, L. U. Sultan, F. Wittatadt, and D. N. Shi~puri. Infectiousness of air from a tuberculosis ward: Ultraviolet irradiation of infected air: Comparative infectiousness of different patients a Am. Rev. Respir . Dis. 85: 511-525, 1962.

393 70. Riley , R. L., W. F. Wells, C. C. Mills, W. Nyks, and R. L. Lean . Air hygiene in tuberculosis: Quantitative studies of infectivity and control in a pilot ward. Am. Rev. Tuberc. Pulm. Dis. 75: 420-431, 1957. 71. Rosenzweig, A. L. Contaminated humidif iers. N. Engl. J. Hed. 283:1056, 1970. 72. Rutter, D. A., and C. G. T. Evans. Aerosol hazards from some clinical laboratory apparatus. Br . Med. J. 1: 594-597, 1972 . 73. Rylander, R., K.-E. Myrback, B. Verner~Carlson, and M. Ohrstr&~. Bacteriological investigation of wall-to-wall carpeting. Am. J. Public Health 62~2) :163-168, 1974. 74 . Sayer , W. J., N . M. MacKnight , and B. W. Wilson. Bospital airborne bacteria as estimated by the Andersen sampler versus the gravity settling culture plate. Am. J. Clin. Pathol. 58:558-566, 1972. Schonborn, C., and F. Winden. Occurrence of fungi in the sir and dust of clinic rooms. Mykosen 16 :385-391, 1973. (in German; English summary) 76. Schulman, J. L. The use of an animal model to study transmission of influenza virus infection. Ame J. Public Bealth 58:2092-2096, 1968 . 77. Scott, C. C., and I. Jacobson. Pseudomonas in ventilators. Lanced 1:239, 1970. 7 8. Seisaburo, S ., K. Kiyoko, and N. Tatsuko. Free dust particles and airborne microflora. Bull. Dept. Home Econ., Osaka City University (Osaka) 4 :31-37, 1959. Sicorenko, G. I. Data on the distribution of Clo~tridium ?erfrin~en~ in the environment of An. Communication I. J. Byg. Epiclemiol. Microbiol. Immunol. (Prague ~ 11 :171-177, 1967. 80. Singh, R. P. Incidence of SaLmonella spp. in poultry farms and hatcheries and their pathogenicity. Indian Vet. J. 44:833-837, 1967. 81. Smith, P. W. Mom humidif iers as the source of Acinetobacter infections. J. Am. fled. Assoc. 237:795-797, 1977. 82. Solomon, W. R. Assessing f ungus prevalence in domestic interiors. J. allergy Clin. Immunol. 56:235-242, 1975. 83. Speers, R., Jr., F. W. O'Grady, R. A. Shooter, B. R. Bernard, and W. R. Cole. Increased dispersal of skin bacteria into the sir after shower baths: The effect of bexach10rophene. Lancet 1:1298-1299, 1966. 84. Spendlove, J. C. Penetration of structures by microbial aerosols. Dev. Ind. Microbiol . 16: 427-436, 1975. 8 5 . Swinne-De~gain, D . Cryptococcus neoformans of saprophytic orig in. Sabouraudia 13: 303-308, 1975. 86. Thacker, S. B., J. V. Bennett, T. F. Tsai, D. W. Fraser, J. E. McDade , C. C. Shepard, K. H. Williams , Jr ., W. B. Stuart, B. B. Dull, and T. C. Eickhoff. An outbreak in 1965 of Revere respiratory illness caused by the Legionnaires' disease bac~certum. J. Infect. Dis. 138:512 - 519, 1978. 87. Tovey, E. R., and R. A. Vandenberg. Effect of reagins and allergen extracts on radioallergosorbent assays for mite allergen. Clin. Allergy 8: 329-339, 1978.

394 88. U.S. Department of Health, Education, and Welfare, National Center for Health Statistics. Acute Conditions. Incidence and Associated Disability, United States, July 1973~June 1974. Data from the National Health Survey, Vital and Health Statistics Series 1G, No . 102. DHEW Publication No. (lIRA)76-1529. Rock~ille, Md.: U.S. Department of Health, Education, and Welfare, National Center for Health Statistics, 1975. 89. Watson, H.H. Errors due to anisokinetic sampling of aerosols. Am. Ind . Hyg . Assoc. Q . 15: 21-25, 1954 . 90. Wells, W. F. Appara~cus for study of the bacterial behavior of air. Am. J . Public Health 23: 58-59, 1933 . 91. Wells, W. F. On air-borne infection. Study II. Droplets and droplet nuclei . Am. J. Hyg . 20: 611-618, 1934 . 9 2. Wells, W. F., M. W. Wells, and T. S. Wilder. The environmental control of epidemic contagion. I. An epidemiologic study of radiant disinfection of air in day schools. Am. J. Byg. 35:97-121, 1942. 93 . Wr ight , ~ . N., E . M. K . Vaichulis , and M. A. Chatigny . Biohazard determination of crowded living~working spaces: Airborne bacteria aboard two naval vessels. Am. Ind. Byg. Assoc. J. 29:574-581, 1968. 9 4 . Young , L. S ., J. C . Feeley, and P. S . Brachman. Vaporized formaldehyde treatment of a textile mill contaminated with Bacillus anthracis. Arch. Environ. Health 20: 400-403, 1970 . ALLERGIC REACTIONS IN THE INDOOR ENVIRONMENT Only a few airborne allergens are found in enclosed ~paces. A1 though human exposure to them is recurrent and of variable duration, the health effects of exposure to them alone are difficult to estimate. Despite this uncertainty, the impact of some agents is clearly appreciable. House dust and pollen, for example, are acknowledged as two of the most important factors in provoking symptoms of allergic rhinitis and asthma in many locales. Clinically evident allergy to animal dancers is due to both the popularity of house pets and the strong sensitizing capacities they exhibit. However, the contribution of other indoor exposures to the overall toll exacted by allergic diseases remains entirely speculative. A broad array of pollens, fungi, algae, actinomycetes, arthropod fragments, dusts, and pumices have been confirmed as airborne antigen sources that evoke human responses; evidence similarly implicating airborne bacteria, protozoa, and other groups is still emerging. Analyses of health impact are further complicated by the varied tissue processes that may be evoked, separately or in combination, by antigen challenge. Particles recovered from indoor air often are assumed to have arisen within the enclosure studied. Bowever, a large proportion of indoor particles reflect natural sources, especially when local growing conditions are favorable. 3 ~~. Inward flux is especially evident for pollen, but also affects interior loads of fungi, insects, and algae . ~ ~ °

395 Allergic reactions can occur on the skin and in the nose, airway., and alveoli. Although increasingly recognized as important causes of allergic lung diseases, occupational agents are considerably less prevalent as causes of these diseases than such allergens as pollen, moulds, mites, and animal dander and excrete, to which exposure occurs i n the home environment . ALLERGIC REACTIONS ON THE SKIN Both primary irritants and allergic sensitizers may produce inflammation of the skin or an eczematous process. Primary irritation causes contact dermatitis. The effect i" through direct action on the skin . Irritants act by removing lipid films, producing denaturation of keratin, or interfering with the barrier layer. Through the production of dehydration, the effects may occur by protein precipitation or oxidation. Sensitizers produce cutaneous changes after previous contacts, either immediately on recontact or shortly thereafter. Almost any chemical may be a sensitizer. A sensitizer stimulates the immune mechanisms by producing an antigen, usually by combining with a protein. Immediate hyperreactivity is produced by a binding with IgE on basal cells. Delayed hyperreactivity may be produced by IgG mediation. 2 3 Photoallerg lo reactions may be produced by ultraviolet (W) light, which leads to an inflammatory response. The antigenic agent may be a UV-mediated degradation product or a Risible-light photosensitized that produces an immediate hypersens itivity response . Secondary effects may occur after the cutaneous defenses have been repoured. Some fatty acids on the surface lipid film may act as antimicrobials. t-3 Bacteria may grow on an oozing or fissured surface. Other toxins may also enter the system at that point. Lesions may be highly variable, with a range from alight inflammation to tumor. Acute contact eczematous dermatitis can be due to a primary irr itant or a sensitizer and is character Sized by inflammation changes, c rusts, and sloughing . ALLERGIC REACTIONS IN THE RESPIRATORY TRACT Allergic reactions in the respiratory tract can be distinguished by the s ite and the nature of the reaction and by the underlying i~maunolog ic mechan isms . S ite and Nature of Reactions Allergic responses to inhaled materials cause a local inflammatory reaction that affects predominantly the nose (allergic rhiniti~), the airways (allergic asthma), the airways and adjacent alveolar spaces (allergic asthma with pulmonary eosinophilia--allergic bronchopulmonary aspergillosis), or alveoli and peripheral bronchioles (hypersensitivity

396 pneu~nitis or extrinsic allergic bronch$oloalveolitis). Similar reactions can occur in each of these separate sites, often producing similar pathologic changes, in the abeen<:e of any recognized extrinsic cause. Allergic rhinitis is characterized be vasodllatatinn and Coma ^F ene nasal mucosa w1tn mucus nypersecretion, which causes nasal discharge and obstruction. Asthma is most usefully defined in functional term as partial narrowing of the airways that is reversible over short periods, either Spontaneously or as a result of treatment. The defining criterion of asthma is therefore variable airway narrowing. This airway narrowing may be due to contractions of airway smooth muscle, edema of the bronchial mucosa, accumulation of bronchial mucosal secretions, or any combination of those. If the cause of the airway narrowing can be identified as an allergic reaction to an extrinsic agent, the tern Allergic asthma. can be used. Pulmonary eosinophilia (pulmonary infiltration with eosinophilis. Or PIE) is defined as transient shadowing on a chest roentgenogram accompanied by an increased blood eosinophil count. Histologically, the alveolar spaces in the affected parts of the lung are consolidated with eosinophila. Pulmonary eosinophilia may be caused by ~ reaction to drugs or to helminthe migrating through the lung. Asperoillus fumigates is the only important inhaled allergen identified as a cause of the syndrome; when it is the cause, the syndrome is called .allergic bronchopulmonary aspergillosis,. or ABPA. ABPA episodes are often accompanied by asthmatic attacks. Hypereensiti~rity pneumonitis is characterized, at least during its early stages, by the infiltration of alveolar walls and peripheral bronchioles with mononuclear cells. The condition is often associated witch the formation of epithelioid and giant~cel1 granulomata. The disease nay be accompanied by progressive fibrosis, which makes it difficult to distinguish the changes in the lung from other causes of alveolar wall f ibrosis . Mechanisms of Reactions Allergic reactions are conventionally distinguished from reactions of protective immunity by the extent of tissue deluge. The immunologic mechanic underlying allergic reactions differ little front those involved in immune reaction.. They are distinguished by outcome: whereas little or no tissue damage occurs in immune reactions, allergic reactions are characterized by the disproportionate damage caused in most tissues. The different types of immunologic reaction that may cause~tissue damage lieve been classified by Gell et al.St Of echoic tour types of allergic reactions, three are of particular tmpormnce in relation to allergic lung diseases immediate (Type T) reactions, Ar thus or local immune complex Type III} reactions, and cell-mediated delayed-hypersensitivity {Type IV) reactions. It ts important to appreciate that, although these types are considered separately, more than one type is involved in most, if not all, cases of allergic lung disease.

39, Immediate (Type I ) Reactions. In this type, antigen reacts with antibody, primarily IgE antibody on the surface of circulating basophils and mast cells, which are present in the sub~ucosa in the nose and airways (as well as in the skin and gastrointestinal tract). IgE antibody is attached to surface receptors on the cell through its Fc portion. Bridging of two adjacent IgE molecules by reaction of antigen with the Fab portion of the molecules stimulate. intracellular metabolic changes that lead to the release of pharmacologically active mediators from the cytoplasmic granules of the cells. The mediators released include histamine and along-reacting substance of anaphylaxis (SRS-A), both of which increase the permeability of small blood vessels to intravascular protein molecules, as well as stimulating smooth-muscle contraction. In addition, eosinophil chemotactic factor of anaphylaxis {ECF-A) is released. The mediators released from these cells during the reaction have pharmacologic properties that could mediate many of the change. observed in the nose and airways in allergic rhinitis and Agatha a . Arthus Local Immune Complex (Type ~ ~ I ~ Reactions . Immune complexes formed in tissue spaces of antigen and IgG antibody in relative antigen excess can cause local tissue damage. Such complexes fix car plement, and several of the complement cleavage product. released have pharmacologic activity. C3a and Cs'~ are anaphylotoxins that stimulate histamine release from mast cells. C 7 is chemotactic both for neutrophils and eosinophils. Neutrophits that have surface receptors for C3b and the Fc portion of IgG phagocytose immune complexes formed in antigen excess when ingested and provoke the release of proteolytic lysosomal enzymes from neutrophils. This in referred to as Regurgitation during feeding. and causes local tissue damage. Thin mechanism is probably important in the tissue damage that occurs in the airways in ABPA and in the inflammatory reaction in alveolar walls in hypersensitivity pneumonitis. Cell-Mediated Delayed-Hyper~ensiti~ritY {Type IV} Reactions. In these reactions, antigen reacts not with antibody, but with specifically sensitized T-lymphocytes. The reaction stimulates the release f rom the lymphocyte of a number of biolog ically active soluble substances known an ~ls~phokinen, ~ which are capable of mediating a local inflammatory reaction . Among these biologic activities, lymphokines have been shown to be chemotactic for macrophages, to induce activation of macrophages, and to inhibit their migration. me interaction of antigen with specifically sensitized T~lymphocytes can therefore stimulate local recruitment and activation of macrophage., in addition to maintaining them at the site of reaction. This type of reaction is well recognized in the delayed hypersensitivity to tuberculin and has also been shown to participate in the infl~tory reaction in alveolar walls in hypersensitivity pneumonitis. Rope IV reactions occur with some bacteria, such as M. tuberculosis. and with fungi, as discussed in the previous section. ~ These immunologic reactions participate in the different allergic reactions to inhaled materials in the respiratory tree, as shown in Table VII-10. Other immunologic mechanisms, not yet clearly identified, may also be involved in these diseases.

398 TABLE Vl I-10 Immunologic Mechanisms in Allergic Lung Diseases Reaction Site Nose Airways Airways and alveolar spaces Alveolar walls and peripheral b ronchiales Disease Allergic rhinitis Allergic rhiniti ~ Asthma with pulmonary eosinophilla, allergic bronchopulmonary asper- gillosis Hypersensi tiv! ty, pneumonic i ~ (extrinsic allergic bronchiolo- alveoli tis To~munologI.c Mechanism 1gE IgE IgE, IgG, immune cow plexes IgG, immune complexes, sensitized T-lympho- cytes

399 FACTORS THAT DETE~NE ALLEPt;IC REACTIONS IN THE ASPIRATORY TRACT . Allergic reactions to inhaled material. in the respiratory tract are determined by a number of identifiable factors, which include the physical and chemical properties of the inhaled particles, the immunologic reactivity of the host, and the pattern of exposure . Na ture of the Inhaled Mater ial Most inhaled materials that stimulate an allergic response in the respiratory tract are particulate and approximately spherical. To cause this kind of response, particles must remain suspended in atmospher ic air long enough to be inhaled; for an immunologic reaction to occur, they must penetrate to a reaction site in the lungs. Inhaled particles are deposited on the surfaces of the nose, airways, and alveoli. Three separate mechanisms contribute to thin deposition: gravitational sedimentation, inertial impaction, and diffusion. Any particles suspended in air will fall under the force of gravity and reach a terminal velocity that is determined by diameter and density. In addition, a particle suspended in an airstream that is changing in direction, as occurs in the nasopharyngeal or branching bronchial airways, will continue for some distance in the original direction of airflow, owing to inertia. The distance traveled by a particle in the original direction of airflow is determined by its density and diameter, the velocity of airflow, and the angle of change of d irection . Impaction of particles due to this; mechanism is of most importance with large particles (aerodynamic diameter, greater than 3 m) In the nose and proxi~1 airways, the portions of the respiratory tract in which the velocity of airflow and angles of change of direction are greatest. Gravitational sedimentation Is of greater importance in determining deposition of smaller particles (aerodynamic diameter, ~ . 5-3 ~n) in the smaller, more peripheral airways and In the alveoli. Very small particles {aerodynamic diameter, less than 1 un) may be deposited by diffusion, owing to their Brownian movement resulting f rom the impact of surrounding gaseous molecules. Most particles who--e aerodynamic diameter is 20 Em or Are and 50% of particles down to 5 am are deposited in the nose. Almost complete deposition of particles of 5 an or more occurs in the tracheobronchial tree. Alveolar deposition (the so-called respirable fraction) is maximal for particles whose aerodynamic diameter is between 2 and 4 A. i- Once deposited, a particle is not resuspended in respired air. Particles not deposited are expelled in the exhaled air. Particles deposited in the airways are trapped in the mucus blanket o n the mucosal surface and are moved centrally by the coordinated beating of the cilia, which extend distally an far as the terminal bronchioles (the ~mucociliary escalators. Some particles deposited in the airways are usually cleared within 24 h. Particles deposited in the alveoli are phagocytosed and cleared by alveolar macrophages; they migrate from the alveoli with their engulfed particles either proximally into the airways on to the mucociliary escalator or out into

doo the draining lymphatica. Clearance of particles deposited in the alveoli takes place in several phases, with characteristic times measured in hours, days, weeks, and years. Of the potentially allergenic particles, the moulde and organic dusts {including animal excrete) have aerodynamic diameters that allow their penetration into the airways and alveoli. The majority of pollens, however, have diameters greater than 12 He, with aerodynamic diameters somewhat different because of their density. Mowesrer, pollen grains have been recovered from the airways by endoacopy and from resected lungs.~°° The chemical properties of ~ molecule that determine its antigenicity are poorly understood. In general, ~complete. antigens that are able to stimulate antibody production are proteins or polyeaccharides of high molecular weight. Both organic and inorganic molecules of low molecular weight {less than 1,000) can act as haptene-, stimulating antibody production when coupled to high-molecular~weight carrier molecules. Immunologic Reactivitv of the It AtopY Coca and Cooke28 introduced the term ~atopy. to describe persons who were Readily sensitized to proteins in their environment. These reactions have since been shown to be mediated by IgE antibody. 67 Peps has redefined ~atopy. as That form of immunological reactivity of the subject in which reaginic antibody, now identifiable as TgE antibody, is readily produced in response to the common allergens of the subject's environment.. The presence of IgE antibody specific to a particular allergen can be demonstrated by its ability to elicit an immediate Weal and flare. skin prick test reaction. The atopic status of a person--but not clinical reactivity--can therefore be defined by reactions to skin tests with allergens appropriate to the particular environment. Several studies38 i28 have show atopy to ~ familial. Its genetic basis, however, remains unclear. Atopy (defined as one or more positive skin test reactions to common inhalant allergens} in asthmatics is strongly related to the frequency in f irst-degree relatives of eczema and hay fever and less to the frequency of asthoa. Circumstances of Exposure to Inhaled Allergens Evidence from the investigations of allergic reaction- to inhaled particles in industry ha. suggested a relationship between exposure and disease. Juniper _ 81.~' shred, in a study of IgE-m~iated allergic reactions to B. subtilis enzymes, particularly alcalase, in the enzyme~detergent industry that the incidence of skin test reactions to alcalase was increased in groups with heavier exposure., but that the incidence in atopics exceeded thee in none topics at each exposure. The effects of differences in intensity and duration of exposure in determining sensitization have not been studied.

401 Exposure to allergens during the early months of life may be important in determining the tendency to produce IgE antibody to inhalant allergens. Taylor et al. iS2 demonstrated an ase~iation between transient IgA def iciency in infancy and later development of atopy. They suggested that inhalant and ingested (particularly milk) allergens traverse mucosal barriers in TgA-deficient persons during this ~vulnerable. period and stimulate the production of IgE antibody. If this hypothesis is correct, it presents an opportunity for the prevention of atopy: exclusion of potential allergens from the environment during this period may prevent the stimulus to IgE product ion . ALLERGIC L=G DISEASES AND THEIR CAUSAL WAS _ ~ Al lergic Rhinitis and Asthma IgE-mediated rhinitis and asthma may be caused by a wide variety of allergens common in the environment, which include the house dust mite, pollens, moulds, and animal Wander and excrete. The particular allergens that cause these diseases have great geographic variation: exposure to different moulds and pollens and to the house dust mite varies greatly according to climatic conditions, which determine their prevalence in a particular environment. Pollen. Among biogenic particles, pollen grains can perhaps be most confidently ascribed to sources in nature, and their presence in enclosed spaces generally reflect. incursions from outdoor air. Wind-pc~llinated plants typically have drab, Scentless, individually minute flowers, unlike the large showy blooms of n any popular house plants . However, with s izable indoor planting , pollens of cyclamen and impatient have been found to reach concentrations of hundreds of grains per cubic meter; their possible effects have not been studied ha. Surge and W. Solonon, unpublished data). The few studies of the flux of pollens into homes have emphasized the importance of free ventilation and indicated that even partial closure of windows can substantially exclude these particles. ' Undisturbed, closed rooms were recognized as pollen ~refuges. many years ago. However, pollen grains are known to enter fully closed structures through faults between structural members (.crackage.~--an effect positively related to outdoor wind speed '2 and probably heavily dependent on gust-induced ef feet'; . The opening of doors as occupants enter and leave further enhances the entrance of pollen and limits the barrier function of any building. After penetrating indoors, pollen may remain airborne or be deposited, with secondary reflotation possibly due to scouring air currents and disturbance of substrates . Many different pollens from grass, trees, and flowers have been shown to cause allergic rhiniti" and asthma. Pollen counts vary greatly during the year and from year to year, and symptoms in sensitized people are closely related to the prevalence of the

402 particular pollen causing disease. Grass and ragweed pollen, which are particularly common causes of allergic rhinitis and asthma, are most abundant in the summer months. In some areas, the pollens of mulberry and other trees are also important. Although soluble extracts of pollen have been shown to provoke asthmatic reactions in symptomatic persons, pollen grains are generally too large to penetrate into the respiratory tract beyond the trachea. Various suggestions bave been made to explain how in these circumstances pollen can penetrate into the airways and react with IgE on the surface of submucosal.mast cells to provoke an asthmatic reaction . Pollen grains and f ragments of pollen grains {or plant bract) may be small enough to penetrate into the airways and have been so found In an autopsy -study. ~°° Kimura et al. Is have identified basophils and mast cells in the lumen of the airways. Inhaled pollen grains may therefore stimulate an IgE-dependent mart cell and basophil degranulation that occurs initially in the bronchial lumen. House Dus t Mite . Interest in acar ids has been stimulated largely by some pyroglyphid mites that contribute sensitizing materials to domestic dusts. House dust is a poorly characterized and variable substance that is universally recognized to produce allergic rhinitis th 77 IS USE In many areas, two mite species. Dermatophagoides pteronYssinus and _ farinae, are abundant indoors and may be recovered from air in domestic interiorse31 78 ~O7 1S' Parallel allergic reactivity to these agents and to crude house dust has been described widely, 10' 10. USE -'and ~" ^~~^~~;^~- ~~~ All' "^ Mayo =~e~ ·-v`~ - "~ c ace ~ documented.73 A possible role for mite allergy has been proposed in urticaria (hives) 33 and in other skin disorder". 62 House dust mites are most abundantly associated with mattresses, bedclothes, and heavily used upholstered furniture. 7 ~ ~ ' ~ s ~ ~ temperature Of around 25.c appears most favorable, and a relative humidity of at least 459 is essential to prevent death from desiccation. Populations vary with atmospheric moisture, often being highest in autumn, but also in sunder or winter, especially in damp houses. 7J 107 15' 1C. ,_,,_,;,, _; I_ .,; art- "~* ~ . , . . _ . ¢] ~ ~ ^] HIl 4" Bus "~. 13" ~ ~ ~ "~ ^~" ~ ^= ·. ~ v" ~ rein especially numan ep~dermal scales; specific fungi may also De favored, 135 but nutritive factors may not be important for concentration. " Indoor temperature does not appear to be important." 107 Mite numbers may be reduced by decreasing indoor humidity, avoiding f ibrous floor and furniture coverings, and encasing pillows and mattresses in plastic. Safe and effective chemical miticides for the home are still needed. Extensive surveys of indoor acarids have disclosed additional commonly recovered genera {G1YCYPhaQUS , Hirstia, Tyropheaus, and Euroglyphus} that inhabit dust. In addition, interiors used to process or store agricultural products often yield large and specialized mite populations. " use I" Although the whole house dust mite is about 300 Am long, the allergens are probably present in its debris, particularly the excrete, whose particles are of an inhalable size.

403 Moulds. The mounds that may cause allergic rhinitis and asthma are predominantly of the genera Alternaria, CladosPorium' and AsPergillus, as well as Merulius lachrYmans, the cause of dry rot. A~spher to spore counts of these moulds are usually highest in the late surmer and autumn, although spore counts of AsPeraillus fu~ainatus are maximal in the autumn and winter. Cladosporium was by far the most frequent taxon recovered both - outdoors and in domestic and other ~clean. interiors during surmer in the United States, :9 '. `' ~ t~ t2 121 12S ~~e is, in Euro" ~ so ~~. ~22 and in Asia,72 but was always more abundant outdoors than indoors.' I ~' Penicillium usually dominated wintertime U.S. collection as 121 ll. l'. and some European site547 `' USE l`. and is often considered an ~indoor. fungus, being frequently more abundant indoors than outdoors. ~ to `, Is 123 Penicillin concentrations also increase - substantially with housecleaning and repair.. 3 ~ 2 2 Alternaria was the most frequent indoor f ungus in the summertime in two southwestern U.S. studies, 3. 85 although the contribution of outdoor air was uncertain. Aspergillus was dominant in only two studies, one in China and one in Great Britain,.. but is considered one of the most common groups of indoor fungi. 25 Aspergillus species were usually other qlaucus groups (e.g., A. amestelodami and A. rePens) or A. versicolor, with relatively few A. fumigates or A. flavus recoveries. Mucor was consistently more frequent indoors than outdoors. Cases of contamination of domestic interiors usually involved outdoor fung i that increased indoors on specific substrates. Floodwater disasters often produce abundant mold growth with attendant increase in airborne spore counts.~9 7' Any organic material may support mold growth when wet. Damp walls may acquire abundant Cladosoorium cladosuorioides and Aureobasidum,., 'I and damp leather, cotton, and paper often are covered with Penicillium or AsPergillus spores. Fireproofing materials, ~ furniture stuffing (e.g., kapok, feathers, and hair 2 ~ ~ S S ~ ~ I), carats, ' ~ and stored organic material ~ ' ~ ~ all have been implicated an foci of mold contamination. House dust contained 10,000-3.000.000 spores/g in one study, ~49 and dust-raising activities clearly increased spore counts in libraries ~ 9 and domestic interiors. ' ~ ~ 2 ~ Repair work increased counts up to 20-fold, presumably because of dust dispersion; and contamination was not restricted to the actual repair site, but spread throughout the home. 98 E'ungal taxa in dust may occur in proportions different from those in air; s, in fact, some fungi may grow in dust. 124 15S Several additional reports have implicated house dust S3 12S t61 as a source of airborne fungi. Mouse plants have been implicated as sources of increased A. fumigates concentrations in hones and hospital rooms; ~4' In' however, Burge and Solomon t unpublished data) did not f ind evidence of this ubiquitous soil fungus in domestic air associated with house plants. Pets have also been blamed for increased A. fumigates counts, ' ~ but Burge et al. 2 ~ did not find evidence of direct animal contributions to the A. fumigates in a series of animal-care rooms. Poor landscaping practices, including accumulation of organic debris and high shade, " and such appliances as

404 evaporative humidifiers 1l' i51 and air~conditionerel.2 165 have been named as potential sources of airborne fungal contamination. The wood-rotting fungus Merulius lacr~uns, contaminating damp timers in old and damaged English homes, may produce potentially sensitizing spores indoors at up to 360, 000/~3 of sir . ~ ~ s ~ Spores released in {or allowed to enter) one area of a hone spread rapidly to s11 areas with open doors.2' The situation differs markedly in interiors used specifically for processing or handling of biologic materials. ~ ~ I? 24 27 l. l. 42 52 S ~ S ~ ~ 5 ~ ~ ~ 1 - ~ ~ ~ J 1 1 0 1 ~ ~ 1 ~ ~ ~ 2 ~ ~ 2 ~ ~ 2 ~ 1. ~ '15 ~ Aspergillus fumigates i8 a ubiquitous 80il fungus and can ~ present wherever organic material provides a suitable subetrate.~' ~~' In outdoor urban air, A. fumigates rarely exceeds 150 spores/m3 and is not necessarily frequent. ii.~ In the presence of compost, counts can rise into the millions per cubic meter,' ts, with the possibility of attendant indoor pollution. In relatively clean interiors, A. fumigates counts generally are low: 0-200/m3.S I' 6' ~ ii~ ~~ Bowever, in interiors in which organic material is stored or handled, they can exceed 2 x 101° spores/m3. ~ 57 s. 65 The incidence of invasive aspergillosis in Me normal population appears quite low, even in persons exposed to spores at high courts, 58 Is but the risk of hypersensitivity disease in overexposed people i8 substantial..-. 50 61 .. l. Il' Ill 1.S 146 Ill A wide variety of fungi that are normally saprophytic (as is A. fumigates) may opportunistically beige invasive human pathogens. 3' Some data on indoor contamination by these organisms are available from general surveys of indoor would concentrations, 2 ~ ~ ~ ~ 2 1 S S S 7 but none has been studied with respect to possible risk factors that foster human infection . Algal Particles. Algal cells, including viable units, are regular components of outdoor aerosol and have been regarded as potential human allergens for decade. '' Algae reside in soil and on natural surfaces, as well as in aquatic habitats, from which they may become airborne in the bursting of bubblesi26 or the fragmentation of Fatima. 127 These processes, as well as dry dis~relon from soil, all increase with rising wind speed and with physical {e.g., agricultural) d isturbance of substrates. ~ ~ Although concentrations of algae in indoor air have not been systematically studied, they are often present in water reservoirs and in house dust and are undoubtedly dispersed periodically. Soil particles and aerosols from water reservoirs are the ~~t probable sources of algae recovered indoors. Sensitization to dustborne green algae (Chlorella sPo.} has been "ply documented however, the impact . . ~ of indoor exposure to these or related organism ream = uncertain. '' Animal Dander and Excreta. Domestic article, particularly cats, are important causes of allergic rhinitis and adieu. Other animals that can cause these disease. include dogs, rabbits, guinea pigs, and horses. It has been generally accepted that the source of allergens t. the animal dander. Recent studies of laboratory-animal workers with rhinitis and asthma due to IgE-aediated reactions to rats and Dice have

405 identified the animals' urine as an important source of allergenic protein. The urine of the other animals has not yet been investigated as a possible source of allergens. Sensitivities to pets are discrete, showing species specificity and often breed specificity. 3.' Washed hair is generally antigen-poor, . but epiaermal scales and body fluids appear to carry potent activity. Highly sensitive persons may develop urticaris or flares of allergic eczema from direct physical contact with the implicated species. Whether airborne antigen alone can cause these skin problems is not clear. However, respiratory symptoms often continue for many weeks after an implicated pet has left the home, and that suggests that minute inhaled doses of dander can sustain a clinical response. Because the airborne antigen has not been measured. more explicit dose-response relationships also remain unknown. Although more commonly associated witch hypersensitivity pneumonitis, \62 serum proteins in the feces of birds, particularly of parakeets (budged igars ~ and pigeons, can stimulate IgE antibody production, especially In atopic per~ons,4° and cause asthma. Feathers, present largely in bedding and clothing, are familiar sensitizers that seem to acquire increasing antigenic potency with age, 9 s although this change could reflect progressive invasion by mites (or microbial contamination); differences between purified antigens of feathers and house dust have been claimed. ~. The offending materials seem to be derived primarily from serum and intestinal secretory components, 36 although feather and egg proteins also may contribute antigens. The cause of rhinitis and asthma associated with an IgE-mediated reaction can usually be readily identified from the history and from skin prick test reactions. A history of symptoms that are temporarily related to a particular exposure Be., seasonal variation in symptoms or symptoms occurring after exposure to domestic animals or bedmakings) strongly suggests the relationship. The presence of IgE antibody specific to the particular allergen will be revealed through skin prick testing with the putative allergens. Fragments of epidermis and Akin appendages (dancers ~ are shed by all vertebrates and undoubtedly are dispersed indoor.. With components of sweat, saliva, and waste discharge", these particles may con~cribute substantial quantities of species-specif ic materials to the indoor environment. Although nontoxic, the dispersed materials are strong sensitizers and commonly elicit allergic rhinitis and asthma. In addition, emanations of birds and of at least one small mammal, the gerbil, 137 have been implicated as agents of allergic alv~litis. Insects . Insect emanations are Strong sensitizer-, can elicit respiratory allergic reactions, and are often evident in outdoor air. Is Symptoms have occurred as a result of local swarming of caddie flies, mushroom flies,74 may fries, 43 and box elder beetles; ~°8 and antibody responses to other types are easily demonstrable . In addition, species that establish themselves indoors--including roaches, houseflies, bedbugs, and carpet

406 beetles--have been implicated as human sensitizers.~. Roaches have received special attention because of their widespread abundance and the capacity of aqueous extracts of common species to elicit respiratory responses in challenged sensitive subjecte.'i Roach fecal pellets appear to share antigens with the bodies of the insects that produce them and, on dissolution, may contribute importantly to air contamination. I' Sensitization to roach antigens is particularly frequent in persons of low income; thin apparently reflects an association with poor sanitary conditions. i2 In addition to Bets, a variety of insects exploited commercially for research purposes can produce indoor contamination and respiratory allergy in exposed persons..' " In' Buman dander. Epidermal scales of human origin are often the most abundant and microscopically distinctive component of indoor dusts. Is S5 These structures readily serve as ~rafts. for aerial transport of bacteria and other microorganisms. However, the role of human dander as an antigen for allergic subjects is highly controversial. Antibody responses to this material have been reported, Is is. but confirmatory data and evidence of clinical impact are still awaited. ~ theta and Pulmonarv Eosinophilia Due to Allergic Broncho~u~mnnarv AsPernillosis ABPA is caused by an allergic reaction in the airways to inhaled AsPer~illus fumigates. The disease i. characterized by recurrent episodes of pulmonary eosinophilia, usually associated with attacks of asthma. In addition to asthma and pulmonary eo~inophilia, as the disease progresses, bronchiectasis (typically proximal, but sometimes widespread), airway narrowing that becomes increasingly less reversible, and pulmonary fibrosis lobes may also develop. that particularly involves the upper asPerqlllus sum~c~atus ~s wlc~elv d~strl~utec~. fits soores are about 3 ~ in diameter, but tend (unlike such other members of the genus an A. clavatus, the cause of malt~worker's lung) to form spore chains up - to 10 am in length, which when inhaled deposit in proximal airways. Unlike the other moulds that may cause asthma, such as the genera Al~ernaria and Clado-oorium, A. fumigates grows at body temperature, and its septate hyphee may be found in sputum. Spore counts are usually highest during the winter, when exacerbations of the disease most frequently occur. In common with such allergens as Dermatophlagoides oteronyssinus and grass pollen, A. fumioatus inhaled into the respiratory tree can stimulate production of specific IgE antibody. Its ability to persist and to grow in the airways can also stimulate IgG antibody production. A. fumigates inhaled into the airways of a person with IgE and IgG antibody not only provoke" release of mediators from mast cells, but can form immune complexes, which in antigen excess cause a local tissue-damaging inflammatory reaction. This is thought to be the cause of the proximal bronchiectasis that is characteristic of the disease.

407 Eosinophil chemotactic factors released from mast cells and from complement activation may be responsible for the associated eo ~ i noph i l ic consol ids t ion . Allergic bronchopulmonary aspergillosis is an unction disease. al~chough in the United Kingdom it is the commonest cause of pulmonary eosinophilia. In one series, it was responsible for 116 of 143 cases of pulmonary eosinophilia . It appears _= ~ ~ less prevalent in the United States than in the United Kingdom. That is probably due to climatic differences: conditions in the United States are generally less favorable to the growth of A. fumigate, although the difference may be due in part to differences in diagnostic convention. The disease should be suspected in those with episodes of pulmonary eosinophilia, usually with Bathe, which occur particularly during periods of the year when A. fumigates spores are most prevalent. Those with asthma whose chest roentgenograms show changes of bronchiectasis or upper lobe fibrosis are also likely to have AREA. BYPersenniti~ritv Pneumanitis (Extrinsic Allergic Alveolitis) Ilyper~en~itivity pne~manitis is an inflammatory reaction in alveolar walls and peripheral bronchioles due to an allergic reaction between inhaled organic particles and circulating antibodies and sensitized lymphocytes. In the acute stages of the disease, alveolar walls and peripheral bronchiole. are infiltrated with mononuclear cells, which form noncascading giant and epithelioid cell granulomata. With progression of the disease (due to repeated or continuous allergen exposure), pulmonary fibrosis, particularly involving the upper lobes, may develop. The disease is thought to be the result both of the formation of immune complexes in antigen excess in alveolar walls and bronchioles and of a reaction between inhaled allergen and sensitized lymphocytes. An increasing number of organic materials have been identified as capable of causing hypersensitivity pneumonitis. Exposure to most of these, such as MicropolYspora faeni (the cause of farmer'" lung}, in Occupational. Two important causes of the disease are nonoccupational: bird fancier's lung and ventilation pne~monitis. Bird fancier's lung is caused by the inhalation of serum proteins in the feces of pigeons and parakeets. The disease may develop in pigeon fanciers or in those who keep parakeets in their homes. Ventilation pneumonitis is due to a reaction to thermophilic actinomycetes growing in ventilation systems; they have been shown to cause hypersensitivity pneumonitis both in offices and in homes with ventilation systems contaminated by these organisms. Thermophilic actinomycetes are not common in outdoor air, but may be extremely abundant in interiors where organic material Is h al al. 23 s' t0 10' I31 and are apparently coon in domestic interiors., 20 Concentrations in barns and cotton mills can exceed 30 oOO/~3 of air ~. 22 23 St ·} ·. 30 10' 131 whereas recoveries in domestic interiors rarely exceed 3,000/m3 . 2 0 Domestic sources of actinomycetes are less clearly identif fed . Thermophilic act~nomycetes have been recovered from humidifier

408 fl id 1. 20 .~_~. .. 130 132 15. 1S'air~Onditioners,' .. 8. 163 and an evaporative cooler.'3 Bowever, their presence In a humidifier doe. not imply dispersion in the air, ' 2. lt~ and airborne "xa may differ from those commonly recovered from humidifier fluid.28 The pattern of symptom in those affected is related primarily to the circumstances of exposure to the causal allergen. Those with intermittent exposure to high concentrations of allergens, as occurs in pigeon fanciers, develop recurrent episodes of breathlessness accompanied by flulike symptoms of malaise, headache, ~algia, and fever. Measurements of lung function during such an acute episode show a restrictive ventilatory defect with a decrease in gas transfer. In the absence of further exposure to the causal allergen, symptoms resolve over a period of 7-10 d, with improvement in lung-function measurements and chest-roentgenogram abnormalities over a month. With further exposures, lung-function tests and radiographic abnormalities can persist, and pulmonary f ibrosis develop. Those who have more continuous exposure to low concentrations of a Ilergen, such as those exposed to parakeet excrete in their homes, often do not develop constitutional symptoms, but later, less r eversible stages of the disease with increasing exertional dyspnea. The abnormalities of lung function are similar deco those found in acute disease: a restrictive ventilatory defect with impairment of gas transfer. There may also be loss of volume of the upper lobes with linear shadows and cystic change due to fibrosis. A disease that is probably due to an allergic reaction in the alveolar wall to contaminants of humidification systems, but which has several important features that distinguish it from typical hypersensitivity pneumonitis, has recently been described and called dehumidifier fever. 37 The particular contaminants responsible are unknown, but may be amebae growing in the water. Those affected have recurrent episodes of flulike symptoms and fever that are often severe enough to overshadow the associated breathlessness. Symptoms develop 4-6 h after the onset of exposure and resolve spontaneously, whether or not exposure continues; and they recur only on reexposure after an absence of several days from exposure. Lung-function measurements during an attack show a restrictive ventilatory defect with impairment of gas transfer that improves over a period of days with the resolution of symptoms, despite continuing exposure. Unlike hypersensitivity pneumonitis, it is not accompanied by abnormalities on the chest roentgenogram during the acute attack, and pulmonary fibrosis does not occur, even in those who have had recurrent episodes of the disease for several years. Precipitins to an extract of the humidifier water or of the ~jelly. growing in the humidifier are found in the serum of those affected, but may also be found in the serum of other exposed persons who do not get the disease. Immunofluorescent antibodies to various species of amebae, particularly Neqleria qruberi and Acanthanoebae, have been found in the serum of those with precipitins deco the humidifier water, but the relationship of these antibodies to disease remains unclear. Concentrations of protozoa in interior air have not been sytematically reported; however, their occurrence indoors from both

409 external and intramural sources nay be anticipated. Protozoa have been recovered, in culture, f rom f ree air by several investigators, as summarized by Schlichting, 127 although the indicated concentrations have been well below those of pollens, algae, and fungal spores. Wind scouring of dry soil has been favored an a source of airborne isolates, although foams and such factors as sewage-proces~ing may contribute locally. 127 Indoor fluid collections--such as aquariums, humidifier reservoirs, and physiotherapy pools--are among the sites of potential colonization by protozoa. Recoveries of an ameba (Hartmannella castellanii) from air in a pediatr ic respiratory-care facility may implicate similar sources; however, many strains of the same species, as well as Nae~leria and SchizopYrenus, also were taken from outside air. " Suspicion has also been cast on protozoa a. agents responsible for humidifier fevers in office and factory workers.35 3' Some species (i.e., Naeglerza fowler and Acanthamoeba spp.) are known to cause dangerous necrologic infections, although aerial transmission has not been demonstrated. 3 S REFERENCES ~- 3. 4. 5. 1 . Ackermann, H . -W., B . Schmidt, and V. Lenk . Mycological studies of the outdoor and indoor air in Berlin. Myko~en 12:309-320, 1969. 2. Acosta, F., Jr., and G. W. Robertstad. Chrysosporium species as fungal air pollutants. Ann. Allergy 42:11-13, 1979. Adams, K. F., and H. A. Hyde. Pollen grains and fungal spores indoors and out at Cardiff. J. Palynol. (Lucknow) 1:67-69, 1965. Aisner, J., S. C. Schimpff, J. E. Bennett, V. M. Young, and P. H. Wiernik. Aspernillus infections in cancer patients. Association with fireproofing materials in a new hospital. J. An. Med. ASsoc. 235: 41}-412, 1976. Ar now, P . M., R. L . Anderson, P . D . Mainous , and E . J . Smith . Pulmonary aspergillosis during hospital renovation. Am. Rev. Respir . Dis . 118: 49-S3, 19?8. Austwick, P. K. C. Ecology of Asperqillus fureigatus and the pathogenic phycomycetes, pp. 644-6S1. In N. E. Gibbons, Ed. Recent Progress in Microbiology . Toronto: Univers ity of Toronto Press, 1963. Banaszak , E . F., J . Barbor iak , J . Fink , G . Scanlon, D. P. Schlueter, A. Sosman, W. miede, and G. Unger . Epidemiologic studies relating thermophilic fungi and hypersensitivity lung syndromes . Am. Rev. Respir . Dis . 110: 58S-591, 1974. Banaszak, E. F., W. H. Thiede, and J. N. Fink. Bypersensiti~rity pnewnonitis due to contamination of an air conditioner. N. Engl. J. Med . 283: 271-276, 1970. Baruah, a. K. The air spore of a cowshed. J. Gen. Microbial. 25:483-491, 1961. 1 0 . Benson , F . B ., J . J . Henderson , and D . E. Caldwell . Indoor- Outdoor Air Pollution Relationships: A Literature Review. U.S. Environmental Protection Agency, National Environmental Research

410 Center Publication No. AP-112. Washington, D.C.: U.S. Government Printing Office, 1972. 73 pp. 11. Bernstein, I. L., and R. S. Safferman. Sensitivity of skin and bronchial mucosa to green algae. J. Allergy 38:166-173, 1966. 12. Bernton, B. S., and H. Brown. Cockroach allergy. T. The relation of infestation to sensitization. South. Med. J. 60:852-855, 1967. 13. Bernton, B. S., and H. Brown. Insect allergy: The allergenicity of the excrement of the cockroach. Ann. Allergy 28:543-S47, 1970 e 14. Berrens, L. On the composition of feather extracts used in allergy practice. Int. Arch. Allergy Appl. Immunol. 34:81-94, 1968. 8errens, L., J. M. Morris, and R. Versie. The complexity of house dust, with special reference to the presence of human dandruff allergen. Int. Arch. Allergy. Appl. Immunol . 27 :129-144, 1965 . Brown, R. M., Jr., D. A. Larson , and H. C. Bold. Airborne algae : Their abundance and heterogeneity. Science 143: 583-585, 1964. Broun, E., and M. Schwartz. S~rampeallergi. Nord. Med. 26: 1219-1225, 1945. 18. Buachner, B. A., A. L. Prevatt, J. Thompson, and O. Blitz. Bagassosis. A review with further historical data, studies of pulmonary function, and results of adrenal steroid therapy. Am. J. Hed. 25: 234-247, 1958. Burge, M. A., J. R. Boise, W. R. Solomon, and E. Bandera. Fungi in libraries: An aerometric survey. Mycopathologia 64: 67-72, 1978. 20. Burge, B. A., W. R. Solomon, and J. R. Boise. Hi<:robial prevalence in domestic humidifiers. Appl. Environ. Microbiol. 39~4~:840-844, 1980. Burge, H. A., W. R. Solomon, and P. Williams. Aerometric study of viable fungus spores in an animal care facility. Lab. Anim. 13:333-338, 1979. 220 Burke, G. W., C. B. Carrington, R. Strauss. J. N. Fink, and E. A..Gaensler. Allergic alveolitis caused by home humidifiers. Unusual clinical features and electron microscopic finding". J. Am. Med. Assoc. 238:2705-2708, 1977. Burrell, R., and M. J. McCullough. Production of thermophilic actino~cete-hay aerosols for use in experimental hypersensitivity pneumonitis. Appl. Environ. Microbiol. 34: 715-719, 1977 . Charpin, J., M. Lauriol-Mallea, M. Renard, and H. Charpin. Study of fungal pollution in bale shops. Bull. Acad. mat. Mid. Paris 155: 52-5S, 1971. {in French) Chen, C. Y., and C-Y. Chuang. Fungi isolated from asthmatic homes in the Taipei area. Chin. J. Microbiol. 8~4) :2S3-258, 1975. 26. Christensen, C. M. Intramural dissemination of spores of Bormodendrum retinae. J. Allergy 21: 409-413, l9SO . 27. Cobe, B. M. Asthma due to a mold. Hypersensitivity due to Cladosporium fulcrum, Cooke. A case report. J. Allergy 3: 389-391, 1931. 2 8. Coca, A. F., and R. A. Cooke . On the cla';sif ication of the phenomenon of hypersensitiveness. J. Immunol. 8:162-183, 1923.

411 29 . Conant , N. F., H . C . Wagner , and F. M. Racken~ann . Rung i found in pillows, mattresses, and furniture. J. Allergy 7: 234-237, 1936. 30. Cooke and vanderVeer, A., Jr. Bean sensitization. J. I~unol. 1: 201-305, 1916. 31. Cunnington, A. M., and P. H. Gregory. Mites in bedroom air. Nature 217: 1271-1272, 1968. 3 2. Dingle, A. N. Meteorological considerations in ragweed hay fever research. Fed. Proc. 16 (2~: 615-627, 1957. 3 3. Dixit, I . P. Dust-mite urticaria. Practitioner 210: 664, 1973. 34 . Dworin, M. A study of atmospheric mold spores in Tucson, Arizona . Ann. Allergy 24: 31-36, 1966. 35 . Edwards, J . H . Bumidif ier fever . Borax 32: 653-663, 1977 . 36. Edwards, J. H., J. J. Barboriak, and J. N. Fink. Antigens in pigeon breeders' disease. Immunology 19:729-734, 1970. 37. Edwards, J. H., A. J. Griffiths, and J. Mullins. Protozoa as sources of antigen in humidifier fever. Nature 264: 438-439, 1976 . 3 8. Emanuel , D. A., B. R. Lawton, and F. J. Wenzel. Maple-bark disease. Pneu~nitis due to Coniosporium corticale. N. Engl. J. Med. 266: 333-337, 1962. Emmons, C. W. Natural occurrence of opportunistic f ungi. Lab. Invent. 11 :1026-1034, 1962. 40. Faux, J. A., L. Wide, F. E. Hargrea~re, J. L. Longbottom, and J. Pepys. Immunolog~cal~aspects of respiratory allergy in budgerigar (Conelopsittacus undulatus) fanciers. Clin. Allergy 1:149, 1971. 41. Feinberg, S. Environmental factors and host responses in asthma. Acta Allergol. 29 (Suppl. 113:7-14, 1974. 4 2. Fergus, C. L. Thermophilic and thermotolerant molds and actinoraycetes of mushroom compost during peak heating. Mycologia 56: 267-284, 1964. 4 3 . Figley, K. D. Asthma due to the Mayfly. Am. J. Med. Sci. 178: 338-345, 1929 . 4 4 . Fink , J . N ., E . F . Banaszak , J . J . Barbor ink , G . T. Hensley, V. P. Kurup, G. T. Scanlon, D. P. Schlueter, A. J. Sosman, W. H. Th iede, and G . F. Unger . Insterstitial lung d incense due to contamination of forced air system. Ann. Intern. ~d. 84: 406-413, 1976. 4 S. Fink, J. N., E. F. Banaszak , W. H. Thiede, and J. J. Barboriak . Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann. Intern. Hed. 74: 80-83, 1971. 46. Fink, J. N., A. J. Resnick, and J. Salvaggio. Presence of thermophilic actinomycetes in residential heating systems. Appl. Microbiol . 22: 730-731, 1971. 47. Flensborg, E. W., and T. Sams~e-Jensen. Studies in mold allergy: 3. Maid spore counts in Copenhagen. Acta Allergol. 3:49-6S, 1950. 48. Frankland, A. W. Locust sensitivity. Ann. Allergy 11:445-453, 1953. 49. Frankland, A. W., and M. J. Bay. Dry rot as a cause of allergic complaint.. Acta Allergol. 4:186-200, l9Sl.

412 50. Gage, A. A., D. C. Dean, G. Schiaert, and N. Hinaley. Aspergillus infection after cardiac surgery. Arch. Surg. 101:384-387, 196700 51 . Gell , P . G . ~ ., R. R. A. Cambe , and P . J . Iacb~ann . Clinical Aspect. of Immunology. 3rd ed. Oxford: Blaclcwell Scientific Publications, 197 5. 1356 pp. 52. Gemeinhardt, B., and I. Bergmann. Houlds in bakery dusts. Zentralbl. Bakter iol ~ Abt. 2 . Naturwiss . 132 s 44-54, 1977. ~ in German; English sun mary) 53. Gravesen, S. Identification and prevalence of culturable mesophilic microfungi in house dust from loo Danish homes. Comparison between airborne and dust-bound fungi. Allergy 33 :268-272, 1978. 54. Gravesen, S. Identification and quantitation of indoor airborne microfungi during 12 months from 44 Danish homes. Acta Allergol. 27:337-354, 1972. 55. Gregory, P. B. The Microbiology of the Atmosphere, pp. 57-70. New York: John Wiley ~ Sons, Inc., 1973. 56. Gregory, P. B., J. H. Hirst, and F. T. Last. Concentrations of basidiospores of the dry rot fungus {Herulius lacrYmans} in the air of buildings. Acts Allergol. 6:168-174, 1953. 57. Gregory, P. B., and M. E. Lacey. Mycological examination of dust from oouldy hay associated with farmer's lung disease. J. Gen. Micropiol. 30:75-88, 1963. 58. Halueg, B., P. Krak'Swks, O. Podaiad~n, J. Owczarek, A. Ponahajbe, and L. Pawlicka. Studies on air pollution by fungal spores at selected working posts in a paper factory. Pneumonol. Polaka 46 :577-585, 1978. 59. Beam, C. E. D.: Bagassosis : An epidemiological, environmental and clinical survey. Br . J. Ind. Iced. 25: 267-282, 1968. 60. Beise, B. A. Symptoms of hay fever caused by algae. J. Allergy 20 :383-385, 1949. 61. Berman, L. G. Aspergillus in patient care areas. Ann. N.Y. Acad. Sci . 353: 140-146, 1980. 62. Hewitt, M., G. I. Barrow, O. C. Miller, F. Turk, and S. Turk. Mites in the personal environment and their role in skin disorders. Br. J. Der~tol. 89: 401-409, 1973. 63. Hill, J., A. Howell, and R. Blowers. Effect of clothing on dispersal of Staphylococcus aureus by Ales and females. Arced 2: 1131-1133, 1974. Hirsch, S. R., and J. A. Sosman. A one-year survey of mold growth inside twelve homes. Ann. Allergy 36: 30-38, 1976. 65. Borej`~, M., J. Mach, A. Tan - sitcom, and A. Mec1. A syndrome resembling farmer's lung in workers inhaling spores of aspergillus and penicillin Suede. Thorax IS: 212-217, 1960. 66. Bughes, W. T., and J. W. Crosier. The rmophilic fungi in the mycoflora of man and environmental air. Mycopatbol. MycO3~. App1. (The Hague) 49 :147-152, 1973. 67. Ishizaka, K., T. Ishizaka, and H. M. Bornbrook. Physiochemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic antibody activity. J. I~unol. 97 :75-85, 1966.

413 68 . Jimenez-Diaz, C., J. M. Ales, F. Ortiz, F. Lahoz, L. M. Garcia Puente, and G. Canto. The aetiologi;c role of molds in bronchial asthma. Acts Allergol . Suppl. 7 :139-149, 1960. 69. Jopke, W. B., and D. R. Amp. Contamination of dishwashing facilities. Hospitals 44 (6) :124-127, March 16, 1970. 7 0. Juniper , C . P., AS. ~ . Mow, B. F. J. Goodwin, and A. K. lCi~holt. Bacillus subtilis enzymes: A 7-year clinical epidemiological and immunological study of an industrial allergen. J. Soc. Occup. ~d. 23:3, 1977. 7L. Kang, B. Study on cockroach antigen as a probable causative agent in bronchial asthma. J. Allergy Clin. Immunol. 58:357-365, 1916. 72. Kanno, S. Indoor contamination by fungi. Japan. J. 8acteriol. 30:458-460, 1975. (in Japanese) 13 . Kawai, T ., D . G . Harsh , ~ . M. Lichtenstein , and P . S . Norman . The allergens responsible for house dust allergy. 1. Comparison of Dermatophagoides pteronyssinus and house dust extracts by assay of histamine release from allergic human leukocytes. J. Allergy Clan. Tmmunol . 50 :117-127, 1972. 74 . Kern, R. A. Asthma due to sensitization to a mushroom fly (Aphiochaeta agarici). J. Allergy 9:604-606, 1938. 75. Rimura, I., Y. Moritari, and Y. Tanizaki. Basophile in bronchial asthma with reference to reagin type allergy. Clin. Allergy 3: 195, 1973 . 76. Kingston, D., and D. C. Warhurst. Isolation of amoebae from the air . ~ . Med . Microbial . 2: 27-36, 1969 . 77. Korsgsard, J. House-du~t mites and allergy to house~dust. Ugeskr. Laeg. 141: 892-897, 1979. (in Danish; English summary) 78. Kors~aard, J. House-dust mites (Ps~roglyphidae, acari) in Danish homes . Ugeekr . I`aeg . 141: 888-892, 1979 . ~ in Danish s English summary) 7 9 . Rozak , P . P ., Jr ., J . Gallup , L . ~ . Cumins , and S . A. Gillman . Factors of importance in determining the prevalence of indoor molds. J. Allergy Clin. Immunol. 61:185, 1978. (Abstract No. 189) 80. Kurup, v. P., J. N. Fink, and D. M. fin. Thermophilic actinomycetes from the environment. Mycologis 68:662-666, 1976. 81. Lacey, J. Microorganisms in air of cotton millet Lance t 2: 455-456, 1977. 82. Lacey, J. Potential hazards to animals and man from microorganisms in fodder and grain. Br. Mycol. Soc. Trans. 65: 171-184, 1975. 8 3 . Lacey, J. The air spore of a Portuguese cork factory. Ann. Occup. Hyg . 16: 223-230, 1973 . 8 4 . Lacey , J ., J . Pepys , and T. Cross . Actinomycete and f ungus spores in air as respiratory allergens, pp. 151-184. In D. A. Shapton and R. G. Board, Eda. Safety in Microbiology. New York: Academic Press, Inc., 1972. 85. Leve tin, E., and D. Burewitz. A one-year survey of the airborne molds of Tulsa, Oklahoma. II . Indoor survey. Ann. Allergy 41: 25-27, 1978. 86. Lidwell, O. M., and W. C. Noble. Fungi and clostridia in hospital air: The effect of air-conditioning. J. Appl. Bacterial. 39: 251-261 1975.

414 J 93. 87 ~ Liebeskind, A. Diagnostic value of culture procedures and provocation tests in suspected mold allergies. Acts Allergol. 26: 106-116, 1971. 8 8. Liebeskind, A. Mold allergy in factories. Allerg. Asthma ( - ipzig) 11:62-65, 1965. (in German; English summary) 8 9. Llamas, R., D. R. Mart, and N. S. Schneider . Allergic bronabopulmonary aspergillosis associated with smoking moldy marihuana. Chest 73:871-872, 1978. 90. I.ockwood, M. G., and R. W. At~well. Thermophilic actinomycetes in air of cotton mills. Lancer 2:45-46, 1977. 91 . Lumpkins, E . D., Sr ., and S . Corbit . Airborne fungi survey . ~ I . Culture plate survey of the home environment. Ann. Allergy 36: 40-44, 1976. 9 2. Lumpkins, E. D., Sr ., S. L. Corbit, and G. M. Tiedeman. Airborne fungi survey. 1. Culture-plate survey of the home environment. Ann. Allergy 31: 361-370, 1973. Mar inkovich , V . A., and A. Hill . Hypersens itivity alveol itis O J . Am. Hed. Assoc. 231: 944-947, 1975. 94. Marsh, P. B., P. D. Millner, and J. M. Kla. A guide to the recent literature on aspergillosis as caused by A. fumigate. USDA Manual ARM-NE-5 . Washington, D.C .: U. S. Department of Agriculture, 1979. 9 5. Mathews, R. P . Other inhalant allergens, pp. 945-956. In E. Middleton, Jr ., C. E. Reed, and E. F. Ellis , Eds . Allergy : Pr inciples and Practice . Vol. 2 . Saint Louis: The C . V. Mosby Company, 1978. 9 6. Matsumura, T., K. Tateno, S. Yugami , and T. Rimura. Four cases of asthma caused by silk inhalation. J. Asthma Res . 4: 205-208, 1967 . 9 7. Maunsell, K. Air—borne fungal spores before and after raising dust. (Sampling by sedimentation. ~ Int. Arch. Allergy App1. Immunol . 3: 93-102, 1952. 98. Maunsell, K. Concentration of airborne spores in dwellings under normal conditions and under repair. Int. Arch. Allergy App1. Immunol. 5: 373-376, 1954. 9 9 . McGovern , J . P ., T . R. McElhenney , and R. M. Brown . Airborne algae and their allergenicity. Part I. Air sampling and delineation of the problem. Ann. Allergy 23:47-50, 1965. 100. Michel, B., J. P. Marty, L. Quet, and P. Cour. Penetration of inhaled pollen into the respiratory tract. Am. Rev. Respir. Dis. 115:609~16, 1977. 101. Hiller: -- M., R. Patterson, J. N. Fink, and M. Roberts. Chronic hypersensitivity lung disease with recurrent episodes of hypersensitivity pneumonit'^~ due to a contaminated central humidifier. Clin. Allergy 6:451-462, 1976. 102. Millner, P. D., P. B. Marsh, R. B. Snowden, and J. F. Parr. Occurrence of Asperqillus fuminatus during comporting of sewage sludge. Appl. Environ. Microbial. 34:765-772, 1977. 103. Mitchell, W. F., G. W. Wharton, D. G. Larson, and R. Medic. Mouse dust, mites and insects. Ann. Allergy 27:93-99, 1969. 104. Miyamoto, T., S. Oshima, and T. Tshizaki. Antigenic relation between house dust and a dust mite, Dermatophagoides farinae

415 Hughes, 1961, by a fractionation method. J. Allergy 44:282-291, 1969 . 1 05. Moore, B. S ., and J. S . Byde. Characterization of breed-specif ic dog dander and serum allergens. J. Allergy Clin. Immunol. 63:206, 1979. (Abstract No. 247) 1 06. Moore , B. S ., J . S . Hyde, and L. M. Manaligod. A comparative study of allergens of canine origin. Ann. Allergy 39: 240-24S, 1977 . 1 07. Murray, A. B ., and P. auk. The seasonal variation in a population of house dust mites in a North American city. J. Allergy Clan. Immunol . 64: 266-269, 1979. 108. Murray, F. J., 11. Brown, and B. S. Bernton. A case of asthma caused by the box elder beetle. J. Allergy 45:103, 1970. (Abstract No. 121 109. Nicholson, D. P. Bagasse workerts lung. Am. Rev. Respir. Dis. 97: 546-S60, 1968. 110. Nilsby, I. Allergy to worlds in Sweden. A botanical and clinical study . Acta Allergol . 2: 57-90, 1949 . 1 11. Noble , W. C ., and Y. M. Clayton. Fungi in the air of hospital wards. J. Gen. Microbiol. 32: 397-402, 1963 . 112. Parlato, S. J. The sand fly (caddie fly) as an exciting cause ot allergic coryza and asthma. II. its relevant frequency. 3. Allergy I: 307-312, 1930. 113. Pepy", J. Atopy, p. 877. In G. M. Gell, R. R. A. Coombs, and P. J. I,achnason, Ed.. Clinical Aspects of Immunology. Oxford: Blackwell, 1975. 114. Perlman, F. Insects as inhalant allergens. Consideration of aerobiology, biochemistry, preparation of material, and clinical observations . J. Allergy 29: 302-328, 1958. 115 . Peterson, J ~ E. Estimating sir filtration into houses: An analytical approach. ASHORE J. 21~1~:60-63, 1919. 116. Popescu, T. G., and E. Capetti. Study of mold spores in houses of asthmatics. Rev. Roum. Hed. Interne (Bucharest) 8: 3S7-361, 1971. 117 . Popescu , I . G., E. Capetti , C. Galalaie, and ~ . Spiegler . Study of atmospheric fungi in a big cereal silo over a period of one year . Rev . Roum. Med . Medicine Interne (Bucharest) 13: 221-226, 1975. 118. Prince, 8. E., M. B. Morrow, and G. M. Meyer. Molds in occupational environments as causative factors in inhalant allergic diseases. A report of two cases. Ann. Allergy 22: 688-692, 1964 . 1 19 . Raper, K. B., and D. I . Fennell. The genus Asper~illu~. Baltimore: The Williams & Wilkins Company, 1965 . 686 pp . 120. Refai, H., and A. Loot. Studies of mould contaminations of meat in slaughter houses, butcher 's shops and in cold stores . Myko~en 12: 621-624, 1969. 121. Richards, M. Atmospheric mold spores in and out of doors. J. Allergy 25: 429-439, 1954 . 122. Ripe, E. Mould allergy. I. An investigation of the airborne fungal spores in Stockholm, Sweden. Acts Allergol. 17:130-159, 1962.

416 123. S~m~sie~ensen, T. Mould allergy. Sensitization by 8peci81 exposure illustrated by two cases of allergy to Cladosporiue fulcrum. Acta Allergol. 9:38-44, 1955. 124. Samson, R. A., and B. van der I`ustgreaf. Aspergillus penicilloides and Eurotium halophilicum in association with house-dust mites . Mycopathologis 64 :13-16, 1978. 125. Schaffer, N., E. E. Seidmon, and S. Bruskin. me clinical evaluation of a~r-borne and house dust fungi in New Jersey. J. Allergy 24: 348-3S4, 1953. 126. Schlichting, B. E., Jr. Ejection of atcr~lgae into the sir via bursting bubbles . J. Allergy Clin. I~unol. 53 :185-188, 1974 . 127. Schlichting, B. E., Jr. T3ne importance of airborne algae and protozoa. J. Air Pollut. Control Assoc. 19: 946-951, 1969. 128. Schlueter, D. P., J. N. Fink, and G. T. Benaley. Wood-pulp workers' disease: A hypersensitivity pneumonitis caused by Alternaria. Ann. Intern. Med. 77: 907-914, 1972. 129. Schwartz, M. Heredity in bronchial asthma. Acts Allergol. 5 (Suppl. lI), 1952. 130. Seabury, J., B. Becker, and J. Sal~raggio. Bome humidifier thermophilic actino~ycete isolates. J. Allergy Clin. I~unol. 57 :174—176, ;~6 ~ 131. Seabury, J.~ -~ ~alvaggio, EI. Buachner, and v. G. Kundur. Bagassosis. III. Isolation of thermophilic and mesophilic actinomycetes and fungi from moldy bagasse. Proc. Soc. Iraq?. Blol. Med. 129: 351 - 360, 1968. 132. Seabury, J., J. Salvaggio, J. Domer, J. Fink, and T. Kawai. Characterization of the rmophilic actinoeycetes isolated flora residential heating and humidification systems. J. Allergy Clin. Tmmunol. 51 :161-173, 1973. 133. Segretain, G. Infection by fungi that ordinarily are saprophytes. Pulmonary aspergillosis. Lab. Invest. 11:1046-1052, 1962. 134. Sherman, H., and D. Merkeamer. Skin test reactions in mold-sensitive patients in relation to presence of molds in their homes. N.Y. State J. Med. 64: 2533-2535, 1964. 13S. Sidranaky, B. Experimental studies with aspergillosis, pp. 165-176. In E. W. Chick, A. Balows, and M. Furcolow, ads. Opportunistic Pungal Infections. Proceedings of the Second International Conference. Springfield, I11.: Charles C Thomas Publisher., 1915. 136. Sinha, R. H., J. 13. M. B. Ran Bronswijk, and B. A. H. Wallace. }louse dust allergy, mites and their funga1 associations. Can. Med. Assoc. J. 103: 300 - 301, 1970. 137. Slavin, R. G., and P. Winzenburger. Epidemiologic aspects of allergic aspergillosis. Ann. Allergy 38:215-218, 1977. 138. Solomon, W. R. Assessing fungus prevalence in domestic interiors. J. Allergy Clin. I~unol. 56:235-242, 1975. 139. Solomon, W. R. Fungus aerosols arising from cold-mist vaporizers. J. Allergy Clin. Immunol. 54:222-228, 1974. 140. Solo~n, W. R., and B. P. Burge. Aspergillus fumigates levels in- and out~of-doors in urban air. J. Allergy Clin. Immunol. 5S: 90-91, 1975.

417 141. Solomon, W. R., B. P. Burge, and J. R. Boise. Airborne ergillus fumigates levels outside and within a large clinical center. J. Allergy Clin. Immunol. 62:56-60, 1978. 142. Solomon, W. R., B. P. Burge, and J. R. Boise. Exclusion of particulate allergens by window air conditioners. J. Allergy Clin. Immunol. 63:215, 1979. (Abstract No. 274) 143. Spendlove, J. C. Penetration of structures by microbial aerosols. Dev. Ind. Microbial. 16:427-436, 1975. 144. Sreeramulu, T. Concentrations of fungus spores in the air inside a cattle shed. Acta Allergol. 16:337-346, 1961. 145. Staib, F., T. Abel, S. K. Mishra, G. Grosse, H. Focking, and A. Blisse. Occurrence of Aspergillun fumigate" in heat Berlin-- Contribu~ ion to the epidemiology of aspergillosis . Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Byg. Abt. 1 Orig. Reihe A 241: 337-357, 1978. ~ in German; English abstract) 146 . Staid, F., U. Folkens , El. Tompak , T. Abel, and D. Thiel. A comparative study of antigens of Aspergillus fumigates isolates from patients and soil of ornamental plants in the immunodiffusion test. Zentralbl. Bakteriol. Parasitenkd. Infektionskr . Byg. Abt. 1 Orig. Reibe A 242: 93-99, 1978. 147. Staib, F., B. Tompak, D. Thiel, and A. Blisse. Aspergillus fumigates and Aspergillus nicer in two potted ornamental plants, cactus (Epiphyllum truncatum) and cl ivia (CliYia miniata) . Biological and epidemiological aspect&. Mycopathologia 66: 27-30, 1978. 148. Stevenson, D. D., and K. P. Mathews. Occupational asthma following inhalation of moth particles. J. Allergy 39:274-283, 1967. 149. Swsebly, M. A., and C. H. Christensen. Molds in house dust, furniture stuff ing and in the air within homes. J. Allergy 23: 370-374, 1952. 150 . Sweet, L. C., J . A. Anderson, Q. C . Callies , and E. O. Coates, Jr. Hypersensitivity pneumonitis related to a home furnace humidifier. J. Allergy Clin. Ioununol. 48 :171-178, 1971. 151. Taylor, A.- N., C. A. C. Pickering, J. Pepys, and M. Turner-Warwick. Respiratory allergy to a factory humidif ier contaminant. Clin. Allergy 6: 411-412, 1976. (abstract) 1 52 . Taylor , B *, A. P . Norman , B. A. Orgel, C . R. Stokes , M. W. Turner, and J. F. Soothill. Transient IgA deficiency and pathogenesis of infantile atopy. Lancet 2 :111, 1973. 153 . Tourville , D. R., W. I. Weiss, P. T. Wertlake , and G. M. Leudermann. Hypersensitivity pneumonitis due to contamination of home humidif ier . J. Allergy Clin. I~unol. 49: 245-251, 1972 . 1 54 . Towey , J . W., H . C . Sweany , and W . ~ . Buron . Severe bronchial asthma apparently due to f ungus spores found in maple bark . J . Am. Med. Assoc. 99: 453-459, 1932. 155. van der Lustgraef, B. Xerophilic fungi in mattress dust. Mycosen 20 :101-106, 1977. ~ in English) 156. van der Herff, P. J. Mould Fungi and Bronchial Asthma. A Mycological and Clinical Study. Springf ield, Ill.: Charles C Thomas, 1958. 174 pp.

418 con Klopotek, A. fiber das Vorko~en und Verhalten van Schimmelpilzen bet der Romp4stierung st;idtischer Abfallatoffe. Antonie van Leenwenhoek J. Microbial . Serol. 28 :141-160, 1962 . ~ in German) 158. Voorhorst, R. The human dander atopy. I. The prototype of auto-atopy. Ann. Allergy 39: 205-212, 1977 . 1 59 . Voorhorst, R., F. T . M. Spiekeman , }I . Verekamp, M. J. Leupen , and A. W. Lykle~. '~e house~dust mite (Dermatophagoldes pteronyssinus) and the allergens it produces. Identity with the house-dust allergen. J. Allergy 39: 325-329, 1967 . 160. Wagner, B. C., and F. M. Rackemann. Kapok and molds: An important combination. Ann. Intern. Hed. 11: 505-513, 1937 . 161. Wallace, M. 13., R. H. Weaver, and M. Scherago. A weekly mold survey of air and dust in Lexington, Kentucky. Ann. Allergy 8: 202-211, and 228, 1950. 162. Warren, W. P. Hypersensitivity pneumonitis due to exposure to budgerigar. . Chest 62 :170-174, 1972 . 1 63 . Weiss , N. S ., and Y. Soleymani . Ilypersensiti~rity lung disease caused by contsminstion of an air-conditioning system. Ann. Allergy 29 :154-156, 1971. 164. Wharton, G. W. Ilouse dust mites. J. Med. Entomol. 12: S77-621, 1976. 165. Wolf, P. T. Observations on an outbreak of pulmonary aspergillosis . ~copathol . Mycol . Appl . 38: 359-361, 1969 . 166. Wraith, D. G., A. M. Cunnington, and W. M. Seymour. me role and allergenic importance of storage mites in house dust and other environments. Clin. Allergy 9:545-561, 1979. 167. Wray, B. B. M,rcotoxin-producing fungi from house associated with leukemia. Arab. Environ. Health 30: 571-573, 197S. 168. Yule, G. N., and S. R. S. Timur. Indoor and outdoor fungal flora of Anakara . MiRrobiyol . BiBl . 11: 355-364, 1977. -

Next: VIII. Effects of Indoor Pollution on Human Welfare »
Indoor Pollutants Get This Book
×
Buy Paperback | $140.00
MyNAP members save 10% online.
Login or Register to save!
  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!