The relation between the concentrations and characteristics of air contaminants in the work place and the resultant toxic doses and potential hazards after their inhalation depends greatly on their patterns of deposition and the rates and pathways for their clearance from the deposition sites. The distribution of the deposition sites of inhaled particles is strongly dependent on their aerodynamic diameters. For normal man, inhaled non-hygroscopic particles > 2 ,um that deposit in the conducting airways by impaction are concentrated on to a small fraction of the surface. Cigarette smoking and bronchitis produce a proximal shift in the deposition pattern. The major factor affecting the deposition of smaller particles is their transfer from tidal to reserve air.For particles soluble in respiratory tract fluid, systemic uptake may be relatively complete for all deposition patterns, and there may be local toxic or irritant effects or both. On the other hand, slowly soluble particles depositing in the conducting airways are carried on the surface to the glottis and are swallowed within one day. Mucociliary transport rates are highly variable, both along the ciliated airways of a given individual and between individuals. The changes in clearance rates produced by drugs, cigarette smoke, and other environmental pollutants can greatly increase or decrease these rates. Particles deposited in non-ciliated airways have large surface-to-volume ratios, and clearance by dissolution can occur for materials generally considered insoluble. They may also be cleared as free particles either by passive transport along surface liquids or, after phagocytosis, by transport within alveolar macrophages. If the particles penetrate the epithelium, either bare or within macrophages, they may be sequestered within cells or enter the lymphatic circulation and be carried to pleural, hilar, and more distant lymph nodes. Non-toxic insoluble particles are cleared from the alveolar region in a series of temporal phases. The earliest, lasting several weeks, appears to include the clearance of phagocytosed particles via the bronchial tree. The terminal phases appear to be related to solubility at interstitial sites. While the mechanisms and dynamics of particle deposition and clearance are reasonably well established in broad outline, reliable quantitative data are lacking in many specific areas. More information is needed on: (1) normal behaviour, (2) the extent of the reserve capacity of the system to cope with occupational exposures, and (3) the role of compensatory changes in airway sizes and in secretory and transport rates in providing protection against occupational exposures, and in relation to the development and progression of dysfunction and disease.

No abstract

A series of about 2200 children who received X-ray treatment for ringworm of the scalp (tinea capitis) during the 1940s and 1950s, and a comparable group of 1400 treated without X ray, have been followed by mail questionnaire for an average of 26 years since treatment to tabulate the incidence of skin cancer. The X-ray treatment consisted of 300-380 R to five overlapping fields on the scalp, to cause complete depilation. This delivered doses of 300-600 rad to various portions of the scalp, with lower doses to the skin of the face and neck. In the irradiated group, 41 persons have had one or more basal cell carcinomas of the scalp or face while only three have been diagnosed in controls. There was a high prevalence of multiple skin cancers in the irradiated group (80 lesions among 41 cases). The minimum latent period for radiation-induced skin cancers was long--about 20 years--and this may be attributable to the young age of the population. The skin cancer risk was particularly pronounced on the face, where there would be more UVR exposure in addition to X-ray exposure. Lightness of complexion proved to be an important factor in the skin cancer risk. In addition, skin cancers were found only among caucasians, even though 25% of the study population were blacks. These findings suggest that UVR exposure levels or sensitivity to such exposure interact with ionizing radiation exposure in defining skin cancer risk.

No abstract

An estimation of the human lung cancer “unit risk” from diesel engine particulate emissions has been made using a comparative potency approach. This approach involves evaluating the tumorigenic and mutagenic potencies of the particulates from four diesel and one gasoline engine in relation to other combustion and pyrolysis products (coke oven, roofing tar, and cigarette smoke) that cause lung cancer in humans. The unit cancer risk is predicated on the linear nonthreshold extrapolation model and is the individual lifetime excess lung cancer risk from continuous exposure to 1 μg carcinogen per m3 inhaled air. The human lung cancer unit risks obtained from the epidemiologic data for coke oven workers, roofing tar applicators, and cigarette smokers were, respectively, 9.3 × 10−4, 3.6 × 10−4, and 2.2 × 10−6 per μg particulate organics per m3 air. The comparative potencies of these three materials and the diesel and gasoline engine exhaust particulates (as organic extracts) were evaluated by in vivo tumorigenicity bioassays involving skin initiation and skin carcinogenicity in SENCAR mice and by the in vitro bioassays that proved suitable for this analysis: Ames Salmonella microsome bioassay, L5178Y mouse lymphoma cell mutagenesis bioassay, and sister chromatid exchange bioassay in Chinese hamster ovary cells. The relative potencies of the coke oven, roofing tar, and cigarette smoke emissions, as determined by the mouse skin initiation assay, were within a factor of 2 of those determined using the epidemiologic data. The relative potencies, from the in vitro bioassays as compared to the human data, were similar for coke oven and roofing tar, but for the cigarette smoke condensate the in vitro tests predicted a higher relative potency. The mouse skin initiation bioassay was used to determine the unit lung cancer risk for the most potent of the diesel emissions. Based on comparisons with coke oven, roofing tar, and cigarette smoke, the unit cancer risk averaged 4.4 × 10−4. The unit lung cancer risks for the other, less potent motor‐vehicle emissions were determined from their comparative potencies relative to the most potent diesel using three in vitro bioassays. There was a high correlation between the in vitro and in vivo bioassays in their responses to the engine exhaust particulate extracts. The unit lung cancer risk per μg particulates per m3 for the automotive diesel and gasoline exhaust particulates ranged from 0.20 × 10−4 to 0.60 × 10−4; that for the heavy‐duty diesel engine was 0.02 × 10−4. These unit risks provide the basis for a future assessment of human lung cancer risks when combined with human population exposure to automotive emissions.

This is the second follow-up study of 2,215 persons who during childhood between 1940 and 1959 had been given x-ray therapy for tinea capitis and of 1,395 persons well matched for age, sex, and race who were treated for the same disease during the same period without the use of x-ray therapy. The major finding of the study was an excess incidence in the irradiated cases of tumors of the head and neck including the skin, brain, thyroid, and parotid. However, between the groups there was no difference in death due to malignant neoplasms or any other cause. Among white patients, a 40% excess of treated psychiatric disorders was observed in the irradiated group, but there was no difference among blacks.

Epidermal cell kinetics and DNA adduct levels, and skin morphological changes were measured following weekly topical applications for 29 weeks of high (16, 32 and 64 micrograms) benzo[a]pyrene (B[a]P) doses to female ICR/Harlan mice, in order to investigate the relationship of these parameters to the timing, incidence and morphology of the elicited tumors. During the tumor latency period, [3H]thymidine labeling index, mitotic index, epidermal cell stacking, incidence of pyknotic and dark basal keratinocytes and labeled mitoses were periodically measured, as were nuclear area and DNA content. DNA adducts in skin epidermis were measured by an ELISA method over a period of 9 weeks of single weekly applications of 64, 32, 16 or 8 micrograms B[a]P. There was an initial linear increase in DNA adducts with dose in the epidermis but the increase was much less steep above 32 micrograms/week. This did not correlate with the sharp rise in tumor response above the 32 micrograms/week dose rate. Cell kinetic changes in response to the 64 micrograms/week dose reached a plateau in the first few weeks of the tumor latent period. There was little epidermal hyperplasia but an associated dose-dependent increase in [3H]thymidine labeling index, mitotic index and incidence of pyknotic and dark cells. This evidence indicated that B[a]P produced extensive cytotoxicity and cell death with regenerative proliferation under these conditions. Giant keratinocytes occurred in all dose groups. Analysis of a labeled mitosis curve indicated that B[a]P produced a G2/M block. There was a marked inflammatory response in the dermis at all B[a]P doses. Mice were observed weekly for tumor formation. Virtually all of the tumors were papillomas on initial appearance and required an average of 8 weeks to convert to carcinomas. The substantial cell killing and regenerative proliferation, and the correspondence between the dose-response patterns for epidermal damage and tumors, together with the initial appearance of tumors in the benign form, a characteristic of the action of promoting agents, provided evidence that the tissue damage associated with the high dose levels of B[a]P used in this study reflected tumor-promoting activity in this mouse epidermal tumorigenesis model. The implication of the results for mathematical models of tumor formation are discussed.

The aerosolized adrenergic (ADR) agent, isoproterenol (ISO), was found markedly to accelerate mucus clearance within the human tracheobronchial tree. Mucus transport was measured by external gamma counting of aerosolized Fe2O3 particles deposited on the mucous membrane during inhalation. Aerosolized epinephrine (EPI), despite its alpha-ADR bronchial vasoconstrictor activity, increased mucus clearance to the same degree as did aerosolized ISO, with its beta-ADR bronchial vasodilator activity. The vehicle used for delivery of the ADR agents, i.e., a H2O aerosol by intermittent positive-pressure breathing (IPPB), itself increased mucus clearance slightly, but did not elicit the enormous increases produced by the ADR agents. Parenteral ISO caused increases in clearances similar to aerosolized ISO and EPI (consistent with different tissue drug levels achieved). Oral atropine delayed clearance, but atropine prior to an ADR aerosol did not alter the mucus transport effect of the ADR agent. ISO and atropine, despite opposite effects on mucus clearance, caused equal bronchodilation. Thus, increased clearance following aerosolized ISO was not dependent on bronchial vasodilation, aqueous aerosol droplets, reflex parasympathetic activation, or bronchodilation, and seems best attributable to increased ciliary beat rate.