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OCR for page 430
APPENDIX ITT
The Effects of Radon Progeny
on Laboratory Animals
Animal studies have been conducted for over 50 yr to examine the
respiratory effects of pollutants in the air of mines. This work, emphasizing
respiratory cancer, has provided important data on exposure-response
relationships and the interactions among the harmful agents to which
miners are exposed. Many of the initial studies were concerned with
early eBects or short-term pathological changes.2~22~29 In many of the
studies, exposures were based primarily on radon-gas concentrations, with
little or no consideration of radon-daughter concentrations, which have
been shown to contribute the greatest radiation dose to the lung. Two
American research centers the University of Rochester and the Pacific
Northwest Laboratory (PNL)and the Compagnie Generate des Matieres
Nucleaires (COGEMA) laboratory in France have contributed most of the
experimental data on radon-daughter inhalation by laboratory animals.
INHALATION STUDIES AT THE UNIVERSITY OF ROCHESTER
Beginning in the 1950s, investigators examined the biological and
physical behaviors of radon daughters and the dosimetry of radon daughters
in the respiratory tract.~20~25 Shapiro3i exposed rats and dogs to radon
alone at several concentrations and to radon with radon daughters attached
to room-dust aerosols. The degree of attachment of radon daughters
to carrier dust particles was shown to be an important determinant of
the alpha-radiation dose to the airway epithelium and that more than
95%0 of the dose to the airway epithelium was due to the short-lived
radon daughters radium A (hippo) and radium C' (hippo), rather than
to the parent radon. In 1953, Cohn et al.9 reported the relative levels of
430
OCR for page 431
EFFECTS OF RADON PROGENY ON LABORATORY AMMALS
431
radioactivity found in the nasal passages, the trachea and major bronchi,
and the other portions of rat lungs after exposure to radon or radon
daughters. The respiratory tracts of animals that inhaled radon with
its daughters contained 125 times more activity than those of animals
that inhaled radon alone. Beginning in the mid-1950s, Morken,25~27
and Morken and Scott28 initiated a series of experiments to evaluate the
biological effects of inhaled radon and radon daughters in mice; later
experiments also used rats and beagles. The negative results of these
studies suggested that alpha irradiation was inefficient in producing tumors
in the respiratory system.
These experiments were noteworthy in describing exposure-dose re-
lationships in the whole lung, in regions of the lung, and in other or-
gans. The paucity of pathological effects did not permit examination of
exposure-response relationships for carcinogenesis, as demonstrated later
by experiments at COGEMA and PNL. In the early experiments, the only
apparent late, permanent changes occurred in the alveolar and possibly
the bronchiolar regions of the lung. They were observed for a wide range
of doses and developed after 3 yr in the dog and 1 and 2 yr in the rat and
mouse, respectively. Some of these changes might have been preneoplastic,
but the high-level exposures (associated with life-span shortening) and the
early termination of experiments precluded further development to neopla-
sia. The influence of the radon-daughter carrier aerosol (laboratory air) on
the results of these experiments is uncertain, but it might have led to more
rapid solubilization of the daughters into blood and a resulting decrease in
irritation or fibrosis, in comparison with ore-dust and silica aerosols.
INHALATION STUDIES AT COGEMA
The studies by Chameaud and colleagues2~8 were begun in the late
1960s and early 1970s to determine whether radon and its daughters in-
duced tumors in rats and to provide experimental data to support the epi-
demiological data on radon-daughter carcinogenesis. Before 1972, rats were
exposed to ambient air that was enriched with radon after passage through
trays of finely ground ore containing 25% uranium. Resulting radon con-
centrations were 0.75 ,uCi/liter; radon-daughter equilibrium factors were
about 30%. With filters and electrostatic purifiers, the equilibrium factor
was reduced to about 1%. Radon-daughter concentrations were calculated
to be around 2,300 and 75 working levels (WL), respectively, for the two
radon-daughter equilibrium conditions.
After 1972, animals were exposed to radon derived from underground
barrels of radium-rich lead sulfate. Radon was pumped by a closed circuit
into a 1-m3 equilibration container and then to two lamb metal inhalation
chambers. Up to 600 rats could be exposed for as long as 16 h when oxygen
OCR for page 432
432
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
was added to the inhalation chambers. The maximum radon concentration
was 1.25 ,uCi/liter, generally at 100~o equilibrium with radon daughters.
By calculation, the maximum radon-daughter concentration was 12,500
WL. Because of radon-daughter deposition on the cages and the hairs of
rats, the disequilibrium of the radon daughters increased as the number
of animals in the inhalation chambers increased. Exposure periods ranged
from about 1 to 10 months; exposure rates ranged from less than 10
to hundreds of working-level months (WLM)/wk, the majority averaging
approximately 200-400 WLM/wk.*
In two major experiments,2 rate were exposed by inhalation to stable
cerium hydroxide or to uranium-ore dust concentrations with and without
radon daughters, at 130 mg/m3, to determine whether the presence of
dust altered the carcinogenic effect of radon daughters. Exposure to
stable cerium hydroxide before exposure to radon daughters shortened the
induction latent period by 2-3 months. Uranium-ore dust (given on days
alternating with days of radon-daughter exposure) appeared to have little
influence on the tumorigenic process, although too few anunals were used
to permit a firm conclusion.5 Radon-daughter exposures varied from 500
to 8,500 WLM. The effect of the radon daughters did not change with
the various equilibrium ratios. These experiments confirmed that radon
daughters alone induced tumors in rats.
Other changes were observed in these experiments. These are given
below.
· After large radon-daughter exposures, large areas of diffuse in-
terstitial pneumonia with hyaline membrane formation and with severe
fibrosis of interalveola~ septa surrounding capillaries were noted. Death
generally occurred within a few weeks to a few months if exposure exceeded
6,000 WLM. No lung cancers were produced.
Animals lived longer after smaller radon-daughter exposures, with
lung carcinomas appearing 12-24 months after the beginning of exposure.
The time to appearance of tumors increased with decreasing cumulative
radon-daughter exposure. Exposures of 2,00~5,000 WLM, delivered over
30~500 h (during 3-4 months), produced the highest incidence of tumors.
Bronchiolar metaplasia occurred at the bronchioloalveolar junction
and in neighboring alveoli. It consisted of large columnar cells with banal
*Some of the exposure values in these French studies have been supplied by
COGEMA investigators and might be different from previously published values. (J.
Chameaud, personal communication to F. T. Cross, 1986.)
OCR for page 433
EFFECTS OF RADON PROGENY ON LABORATORY ANIMALS
433
nuclei and light-colored protoplasm that were often ciliated. Alveolar meta-
plasia of cuboidal cells, with darker protoplasm, appeared in peripheral
regions of the lungs.
· Adenomatous lesions of varied size and cell layers covered areas of
the alveolar septa. Adenomas consisting of round tumors with cells often
clustered together occurred. Some adenomas showed malignant character-
istics.
Malignant tumors of several different types occurred, often in the
same animal. These included epidermoid carcinomas, not always clearly
differentiated, often keratinized or necrosed, and occasionally extending
into the mediastinum; bronchiolar adenocarcinomas, sometimes mucus-
producing, containing numerous cellular anomalies, and characterized by
a high number of mitoses and invasion of other lung lobes, but seldom
metastatic; and bronchioloalveola~ adenocarcinomas with few mitoses, but
later invading the mediastinum, diaphragm, and thoracic wall.
.
.
The relationship of exposure to tumor incidence, uncorrected for
life-span shortening, was not linear over a wide range of exposures; the
incidence per unit exposure increased with decreasing high cumulative
exposure.
Later experiments, which confirmed these pathological findings,
extended the radon-daughter exposures to approximately 20-50 WLM.5 7~8
Tumor-incidence and survival-time data and lifetime lung-tumor risk coef-
ficients are shown in Table III-1. Although the risk data are uncorrected
for life-span shortening, hazard-function analysis demonstrated that when
the data are adjusted for competing causes of death, the excess risk of de-
veloping pulmonary tumors is approximately linearly related to exposure
throughout the range of exposures studied.~9 Further findings are given
below.
· The tumor latent period, defined as the interval between the start
of radon-daughter exposure and death or killing, of the anneal increased
with decreasing cumulative WLM. Mean latent periods of tumor-bearing
animals were around 750 days for exposures of less than 300 WLM and
650 days for exposures of over 1,000 WLM.
Lung cancers in rats invaded pulmonary lymph nodes, but metas-
tases to other tissues were rare. Tumor size increased with increasing
cumulative WLM.
No radiation-induced small-cell carcinomas were observed in rats:
however, other histological types of lung carcinomas were similar to those
observed in humans.
OCR for page 434
434
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OCR for page 435
EFFECTS OF RADON PROGENY ON LABORATORY ANIMALS
435
· Cutaneous epitheliomas of the upper lip and cancers of the urinary
system were the only two sites other than the lungs where cancers were
noted in exposed rats.
The incidence of lung cancer increased with decreasing high radon-
daughter exposure rate. The greatest effect was noted in exposure-
fractionation experiments. Rats exposed to radon daughters for approxi-
mately 3,000 WLM, at 1,500 WL for 7 in/day or 1 or 5 daystwk (average
exposure rates are calculated to be above 50 and 300 WLM/wk) had a
nearly fourfold increase in cancer incidence with exposure protraction.
While the latency period decreased, the lung-cancer incidence
did not change with increasing age at first exposure. For 3,000-WLM
exposures, the latent periods for ages at first exposure of 150, 280, 400,
and 520 days were 640, 510, 450, and 305 days, respectively.
· Synergism was observed between exposure to radon progeny and
whole-body cigarette-smoke exposures if the exposure to smoke followed the
exposure to radon daughters. However, if the cumulative cigarette-smoke
exposure preceded the radon-daughter exposure, no increase in cancer
incidence was noted over that produced by radon daughters alone. Thus,
the effect of cigarette smoke depended on the sequence of exposures and
was attributed to its promoting action.5 The histological types of cancers
observed were not altered by cigarette-smoke exposures. The investigators
have not reported whether the latent period for cancer was influenced
by smoke exposure; the observation that tumors in the radon-daughter-
and smoke-exposed anneals were larger and more invasive than those in
animals exposed only to radon daughters might be indicative of a shorter
latent period for smoking-related tumors.
The COGEMA studies have produced more than 800 lung cancers in
about 10,000 rats exposed to radon daughters with ambient aerosols and in
mixtures with other pollutants. The exposure-response relationship data
shown in Table III-1 therefore constitute only a portion of the data from
these experiments. The derived range in mean lifetime risk coefficients,
uncorrected for life-span differences from control animals, ~ about 1.5 x
10-4-7.5 x 10-4/WLM for exposures between about 20 and 5,000 WLM.
The risk decreases at larger exposures because of life-span shortening. No
evidence of a threshold below 20 WLM was apparent.8
OCR for page 436
436
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
INHALATION STUDIES AT
THE PACIFIC NORTHWEST LABORATORY
Exposures of dogs and rodents to uranium-mine air contaminants were
begun in the late 1960s and early 1970s to identify agents and the mag-
nitude of exposures to them that were responsible for producing lesions
of the respiratory tract similar to those observed in uranium miners. The
early experiments concentrated on lifetime inhalation exposures of ham-
sters and beagles to mixed aerosols of radon, radon daughters, carnotite
uranium-ore dust, diesel-engine exhaust, and cigarette smoke. Most of the
final data from these early experiments have been published.' t-~3 To pro-
vide data that were missing from the earlier dog study, follow-up studies
have included exposures of beagles to uranium-ore dust alone (but not to
radon daughters alone) and exposures of rats to mixtures of radon, radon
daughters, and uranium-ore dust.~0~4-~8~33 Because the studies in rats
were designed to develop exposure-response relationships, the exposures
were truncated rather than extended through the animals' lifetimes. They
were also designed to study the roles of carnotite uranium-ore dust con-
centration and radon-daughter exposure rate, unattachment fraction, and
disequilibrium in the production of lung lesions. Histopathological exami-
nation, clinical pathological examination, and pulmonary physiology tests
were the primary means of measuring response. Urinalyses have recently
supplemented serum tests as more sensitive evaluations for kidney damage.
Radiometric analyses of tissues have been used to determine mean radon-
daughter tissue doses and the body distribution of long-lived radioactivity
from the ore dust.
Lifetime exposures of hamsters to radon daughters alone or in com-
bination with uranium-ore dust and diesel-engine exhaust caused no sig-
nificant (P > 0.05) changes in mortality patterns compared with those of
controls. The mean radon-daughter exposure in the hamster experiments
was about 10,000 WLM. Lifetime exposures of beagles to mixtures of
radon daughters, uranium-ore dust, and cigarette smoke caused significant
life-span shortening compared with that of controls. Mean survival times
of the dogs exposed to mixtures of radon daughters and ore dust, with or
without cigarette smoke, were 4-5 yr. Mean survival times of controls and
dogs exposed to smoke only were equivalent during the same period. The
mean radon-daughter exposure of the dogs was about 13,000 WLM.
Studies in progress show that chronic exposure of rats to mixtures of
radon daughters and uranium-ore dust shortens the life span. The data thus
far generally show no significant differences in mortality patterns compared
with those of controls for exposures up to about 2,500 WLM. Exposures
exceeding 5,000 WLM have caused significant life-span shortening, with
OCR for page 437
EFFECTS OF RADON PROGENY ON LABORATORY ANNUALS
437
the eBect increasing with exposure. In general, rats that showed life-span
shortening also showed weight loss.
Thus far, two life-span-shortening anomalies have been noted in the
rat experiments. First, in an interim study to determine any influence
of radon-daughter exposure rate, rats exposed to about 640 WLM at the
lowest rate (about 44 WLM/wk) died earlier than other animals given
comparable cumulative exposures. Second, in a study to determine the
influence of unattached radon daughters versus that of attached radon
daughters, rats exposed to about 5,100 WLM with the highest unattach-
ment fraction (fa = 24%) died earlier than other animals given comparable
cumulative exposures. Life-table analyses of the survival-time data in the
unattachment-fraction study showed that the estimated probabilities
that a rat would die with a lung tumor before 600 days were 0.42, 0.65,
and 0.75 for 6, 10, and 24% limo (radium A) unattachment, respectively.
Expressed as percentages of radon concentration, rather than radium A
concentration, the unattachment was 1.3, 5.2, and 9.5%. Later experiments
at 640 and 53 WLM/wk showed no appreciable life-span shortening.
The mean survival time of tumor-bearing rats (as in the COGEMA
data) was always significantly longer than that of non-tumor-bearing rats.
The latent period of lung tumors iB a large fraction of the rat life span,
and tumors must grow to a size sufficient for detection; the shorter-lived
animals might have died too soon for tumors, if any, to be detected.
In the life-span studies with dogs, animals with tumors of the respi-
ratory tract generally had cumulative radon-daughter exposures exceeding
13,000 WLM; the exposure rate was 71 WLM/wk. Concomitant exposure
to cigarette smoke had a mitigating effect on radon-daughter-induced tu-
mors, possibly because smoking caused thickening of the mucus layer and
stunulated mucociliary clearance. The overall incidence of lung primary tu-
mors was 21% for a mean exposure of 13,100 WLM to radon daughters, 37%
in the group exposed to radon daughters and uranium-ore dust, but only
5% in the comparable group that was also exposed to cigarette smoke. The
overall incidence of nasal carcinoma was 8%. The lung cancers were about
70% bronchogenic carcinomas and 30% bronchioloalveolar carcinomas.~5
The sunplified convention used was that squamous cell carcinomas and
mucus-staining adenocarcinomas were bronchogenic carcinomas and that
tumors of Clara cell or type II alveolar cell origin and non-mucus-staining
adenocarcinomas were bronchioloalveolar carcinomas.
Lifetime inhalation exposures of hamsters produced severe radiation
pneumonitm but only four squamous cell carcinomas (three in the radon
daughter~only group and one in the group exposed to radon daugh-
ters and uranium-ore dust) in 306 radon-daughter-exposed animals (1.3%
OCR for page 438
438
HEALTH RISKS OF RADON AND OTHER ALPHA-E~IITTERS
incidence). Squamous cell carcinoma occurred only in association with
squamous metaplasia of the alveolar epithelium, which was found only in
hamsters exposed to radon daughters. Thus, it appears that after expo-
sure to radon daughters, the development of squamous metaplasia and the
development of carcinoma were related. Because so few lung cancers were
produced in these high-exposure experiments, it was concluded that the
hamster was an inappropriate surrogate for further study of the carcino-
genic potential of inhaled (as opposed to instilled) mine-air pollutants.
Over 4,000 male rats have received chronic exposures to ambient air or
to mixtures of radon daughters and uranium-ore dust since 1978. Data are
still accumulating, but some general trends can be observed. Lung-cancer
risk tended to increase (sometimes significantly) with decreasing radon-
daughter exposure rate, increasing unattached fraction of radon daughters,
and increasing radon-daughter disequilibrium. The lung cancers induced
after exposures of approximately 300 5,000 WLM were about 70% bron-
chogenic carcinomas and 30% bronchioloalveolar carcinomas. The tumors
were most often estimated (by sizing associated bronchi and bronchioles) to
be about 50% proximal (bronchus-associated) and 50% distal (bronchiole-
and alveolus-associated), in contrast with the greater proportion of proxi-
mal lung cancers in humans.30 The prevalence of squamous metaplasia, and
generally carcinoma, of the respiratory tract increased with an increasing
unattached fraction of radon daughters.
The PNL data are inadequate for firm conclusions regarding the effect
of radon-daughter exposure rate and the magnitude of the lifetime risk
coefficient below 100 WLM. However, the data to date indicate an increas-
ing lifetime lung-tumor risk coefficient with decreasing cumulative radon-
daughter exposure. Like the COGEMA data, the PNL risk-coefficient data
have not been corrected for life-span shortening due to competing causes
of death, such as radiation pneumonitis (see Table III-1. It cannot be
concluded that the increase in the risk coefficient continues with further
decreases in cumulative exposure and exposure rate. The PNL experiments
include exposures as low as 20 WLM. The tumor-incidence data, partic-
ularly those derived from high-exposure-rate experiments, are similar not
only to those from COGEMA but also to present estimated lung-tumor
incidence data in humans.
Animal exposure studies show that the tumorigenic efficiency of radon
daughters varies with cumulative exposure, exposure rate, unattached frac-
tion, disequilibrium, and concomitant exposures to other pollutants (i.e.,
cigarette smoke). The COGEMA and PNL data indicate that tumor
incidence increases with an increase in radon-daughter cumulative expo-
sure and a decrease in radon-daughter exposure rate. Chameaud et al.5
OCR for page 439
EFFECTS OF RADON PROGENY ON LABORATORY ANIMALS
439
concluded that lung-cancer incidence at comparable cumulative exposures
increased as the radon-daughter concentration decreased from 12,000 to
less than 3,000 WL. In a related dose-fractionation study with a cumulative
exposure of 3,000 WLM and a radon-daughter concentration of 1,500 WL,
an approximately fourfold increase in lung cancers was observed when the
exposure rate decreased from about 300 to 50 WLM/wk; it is not known
whether this exposure-rate dependence persists at the far lower rates. A
trend toward increasing a lung-tumor risk with decreasing exposure rate
was noted in the earlier PNL rat experiments when the rates changed
from 180 to 88 and to 44 WLM/wk. Inasmuch as the increase was not sig-
nificant and results were uncertain at 44 WLM/wk as a result of life-span
shortening in that group, the exposure-rate dependence in rats might be
lessened at the lower weekly rates of exposure. However, more recent data
confirm the increase in lung-tumor risk with decreased exposure rate down
to 53 WLM/wk.
Data from the PNL rat experiments also indicate an increase in the risk
of lung tumors with increases in radon-daughter unattached fraction and
disequilibrium. The risk increase from 1.6 to 10%0 unattached radium A is
significant (P < 0.05), but the positive trend reverses at 24% unattachment
as a result of life-span shortening in that exposure group. In contrast with
the results of the COGEMA experiments, the increase is also significant
with radon-daughter disequilibrium (an equilibrium of 10 versus 40%) when
the total numbers of lung cancers are compared. However, the trend is of
borderline significance (P = 0.10) when the total numbers of rats with lung
tumors are compared. The data on nasal carcinoma show an increasing
trend with increasing unattachment and, as with the neoplastic lesions of
the lung, a reverse trend at 24% unattachment. There is no indication that
high-disequilibrium radon-daughter exposures, without concomitant high
unattachments, produce more nasal carcinomas than do low-disequilibrium
exposures.
The role of concomitant exposures to other pollutants depends not
only on the nature of those pollutants but also on the sequence of exposures.
Simultaneous or same-day exposure to radon daughters and uranium-ore
dust, diesel-engine exhaust, or cigarette smoke increased the incidence of
preneoplastic lesions but, except for cigarette smoke, did not change the
incidence of lung tumors in the PNL experiments. In the COGEMA rat
experiments, cigarette smoke was cocarcinogenic with radon daughters if
exposure to smoke followed completion of exposure to the radon daughters,4
but not if smoking preceded the radon-daughter exposures. In the PNL dog
experiments, lung-tumor incidence decreased when animals were exposed
to radon daughters and cigarette smoke alternately on the same day.
OCR for page 440
440
l o -3
~ o-5
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
_
' '''"'I ' ' '''"'I
· COGEMA Rat Data
O PNL Rat and Dog Data
.
~ O
· O
~0
·0
o
o
o
O Doge
Nonsmoking
O Dogs
Smoking
100
1000 10000 100000
WLM Exposure
FIGURE III-1 Lifetime risk coefficients for radon-daughter exposure for PNL rat
and dog data and COGEMA rat data; error bars are omitted. SOURCE: Personal
communication, Dr. F. Cross, Pacific Northwest Laboratories.
LUNG CANCER
In Figure III-1 the mean lifetime lung-tumor risk per WLM (uncor-
rected for life-span differences from control animals) is plotted against the
radon-daughter exposure (WLM) for PNL rats and dogs and COGEMA
rats. The higher tumor efficiencies in the PNL studies (in contrast with
the COGEMA studies) are probably due to the lower average exposure
rates of the PNL experiments.
The uncertainties in the PNL lung-cancer incidence and risk-coefficient
data are considered to be due mainly to uncertainties in the expo-
sure data (standard deviations were generally well within +20% of the
means). Whenever PNL exposures were repeated, reproducibility of tumor-
incidence data was generally within +20% of the mean tumor incidence,
which included the statistical uncertainties in the exposure data. Because
the normal lung-tumor incidence in the absence of appreciable background
radon exposures is very low (<0.2%) in the COGEMA and PNL rats, the
risk-coefficient data, except for the 20- to 50-WLM COGEMA group of
rats, have not been corrected for the incidence in control animals.
OCR for page 441
EFFECTS OF RADON PROGENY ON LABORATORY ANIMALS
441
Current experiments at PNL, which involve mixtures of radon daugh-
ters and uranium-ore dust, will further define the shape of the risk-
coefficient curve for very low exposures and exposure rates. For the
present, COGEMA data on low exposures and low exposure rates indicate
a leveling-off of the risk to a value of 6 x 10-4 - x 10-4/WLM.
Kushneva23 reported that rats given 50 me of silica by instillation
with inhalation exposures to radon at 8 psi/liter developed many more
pulmonary effects, including both adenomas and carcinomas, than did
anneals exposed to silica alone; the number of tumors and control animals
was small. When silica dusts were included in the exposures, the radon-
daughter inhalation studies at COGEMA and PNL showed no increased
tumorigenic efficiency over exposures to radon daughters alone if these
exposures exceeded a few hundred WLM. However, in contrast with the
rat data of Kushneva23 and the dog data from PNL, Chameaud et al.5
have not found the silicotic process to be accelerated by the presence of
radon daughters.
Little et al.24~32 have shown in hamsters that when benzo~aJpyrene or
saline instillations followed low-dose Echo instillations, the carcinogenic
action of polonium was increased. Because radioactivity appears to be
the initiator of the lung cancer, as in all the animal experiments with
radon described here, any later exposure to an irritant that stimulates cell
proliferation appears to increase the incidence of cancer.
SUMMARY AND CONCLUSIONS
Laboratory animal research programs on the effects of radon-daughter
inhalation are being carried out in laboratories in both the United States
and EYance. While much of the early work explored acute effects, more
recent experiments involving chronic exposure have resulted in the induc-
tion of lung cancer in both rats and dogs. It should be noted, however,
that the location and histopathology of such cancers are not analogous
to humans, and caution is warranted in extrapolating from experiments
with laboratory animals to humans. Nevertheless, substantial information
has accumulated that provides insights into radon-daughter carcinogene-
sis. Table III-2 summarizes recent findings in animal studies of lung-cancer
induction by radon decay products.
In rats, lung tumors have been induced at relatively low exposures
(20 WLM).7 As yet, experiments with dogs do not extend to this low-
dose range, but tumors have been observed for exposures at the 60() WLM
level.~3 It is of interest that lung-cancer incidence in animals increases with
a decreasing rate of exposure for fixed cumulative exposure a finding that
has yet to be confirmed in studies of exposed underground miners (Annex
2AJ. The difficulty of documenting exposure rate for the miners may
explain the failure to find a dose-rate effect in the epidemiological studies.
OCR for page 442
442
HEALTH RISKS OF RADON AND OTHER ALPHA-~MITTERS
TABLE III-2 Summary of Factors Influencing the Tumorigenic Efficiency
of Radon-Daughter Exposure
Factor
Effect on Respiratory Tract Tumor Incidence
Increases approximately linearly with exposure
Increases with decrease in exposure rate ( ~ 200
to 400% increase from about 500 to 50 WLM/
wk)
Increases with increase in unattached fraction, fa
(~50~o increase per WLM exposure from 2 to
loo fa)
Increases with increase in disequilibrium (~30~o
increase per WLM exposure [borderline
significance] from 0.4 to 0.1 equilibrium).
Decreases if smoking alternates on same day with
radon-daughter exposures
Radon-daughter cumulative exposure
Radon-daughter exposure rate
Radon-daughter unattached fraction
Radon-daughter disequilibrium
Concomitant exposure to cigarette smoke
Increases if smoking follows cumulative radon-
daughter exposures
No effect if smoking precedes cumulative radon-
daughter exposures
Large-scale anneal studies may become useful for elucidating the ~nter-
actions between radon daughters and other inhaled pollutants. Information
on the extent and duration of smoking Is incomplete for human studies,
but smoking can be controlled In experunents with anunals. It Is clear from
such experunents that the interactions between smoking and lung cancer
induced by radon decay products reflect a complex interplay of these agents
in the host. Well thought out expeFunents with dogs and rats can provide
models that aid our understanding of how smoking modulates radiogenic
lung cancer. Nevertheless, application to humans is indirect, and confirm-
ing experunents with prunates may be necessary. However, findings In
humans and animals to date are generally parallel for short-half-life radon
progeny.
REFERENCES
1. Bale, W. F. 1951 Hazards associated with radon and thoron. Division of Biology
and Medicine, U.S. Atomic Energy Commission, Washington, D.C.: March 14.
Memorandum. (Also found in Health Phys. 38:1061, 1951.)
2. Chameaud, J., R. Perraud, J. Lafuma, R. Mane, and J. Pradel. 1974. Lesions
and lung cancers induced in rats by inhaled radon-222 at various equilibriums
with radon daughters. P. 411 in Experimental Lung Cancer. Carcinogenesis and
Bioaseays, E. Karbe and J. F. Park, ede. New York: Springer-Verlag.
3. Chameaud, J., R. Perraud, J. Chretien, R. Masse, and J. Lafuma. 1976.
Lung cancer induced in rats by radon and its daughter nuclides at different
concentrations. P. 223 in Biological and Environmental Effects of Low Level
Radiation, Vol. II. Publication STI/PUB/409. Vienna: International Atomic
Energy Agency.
4. Chameaud, J., R. Perraud, J. Chretien, R. Masse, and J. Lafuma. 1980.
Combined effects of inhalation of radon daughter products and tobacco smoke.
OCR for page 443
13FFECTS OF RADON PROGENY ON LABORATORY ANIMALS
443
P. 551 in Pulmonary Toxicology of Respirable Particles, CONF-791002, C. L.
Sanders, F. T. Cross, G. E. Dagle, and J. A. Mahaffey, ede. Springfield, Va.:
National Technical Information Service.
5. Chameaud, J., R. Perraud, R. Masse, and J. Lafuma. 1981. Contribution of
animal experimentation to the interpretation of human epidemiological data. In
Proceedings of the International Conference on Radiation Hazards in Mining:
Control, Measurement and Medical Aspects, M. Comes, ed. Kingsport, Tenn.:
Kingaport Press, Inc.
6. Chameaud, J., R. Perraud, and J. Lafuma. 1982. Cancers induced by Rn-222
in the rat. In Proceedings of Specialist Meeting on Assesement of Radon and
Daughter Exposure and Related Biological Effects, G. F. Clemente, A. V. Nero,
F. Steinhausler, and M. E. Wrenn, ede. Salt Lake City, Utah: RD Press.
Chameaud, J., R. Masse, and J. Lafuma. 1984. Influence of radon daughter
exposure at low doses on occurrence of lung cancer in rate. Radiat. Prot.
Dosimetry 7:385-388.
8. Chameaud, J., R. Masse, M. Morin, and J. Lafuma. 1985. Lung cancer induction
by radon daughters in rate. Pp. 35~353 in Proceedings of the International
Conference on Occupational Radiation Safety in Mining, Vol. 1, H. Stocker, ed.
Toronto: Canadian Nuclear Association.
9. Cohn, S. H., R. K. Skow, and J. K. Gong. 1953. Radon inhalation studies in
rate. Arch. Ind. Hyg. Occup. Med. 7:508.
10. Cross, F. T. 1984. A Review of Radon Inhalation Studies in Animals with Ref-
erence to Epidemiological Data. Research Report for SENES Consultants, Ltd.,
Ontario, Canada. Richland, Wash.: Battelle, Pacific Northwest Laboratories.
11. Cross, F. T. R. F. Palmer, R. E. Filipy, R. H. Busch, and B. O. Stuart. 1978.
Study of the Combined Effects of Smoking and Inhalation of Uranium Ore
Dust, Radon Daughters and Diesel Oil Exhaust Fumes in Hamsters and Dogs.
PNL-2744. Springfield, Va.: National Technical Information Service.
Cross, F. T., R. F. Palmer, R. H. Busch, R. E. Filipy, and B. O. Stuart. 1981.
Development of lesions in Syrian golden hamsters following exposure to radon
daughters and uranium ore dust. Health Phys. 41:135-153.
Cross, F. T., R. F. Palmer, G. E. Dagle, R. E. Filipy, and B. O. Stuart. 1982.
Carcinogenic effects of radon daughters in uranium ore dust and cigarette smoke
in beagle dogs. Health Phys. 42:35-52.
14. Cross, F. T., R. F. Palmer, R. H. Busch, and R. L. Buschbom. 1982. Influence of
radon daughter exposure rate and uranium ore dust concentration on occurrence
of lung tumors. Pp. 189-197 in Proceedings of Specialist Meeting on Assessment
of Radon and Daughter Exposure and Related Biological Effects. Salt Lake City:
Salt Lake City Prep.
15. Cross, F. T., R. F. Palmer, R. H. Busch, G. E. Dagle, R. E. Filipy, and H.
A. Ragan. 1983. An overview of the PNL radon experiments with reference
to epidemiological data. In Proceedings of the 22nd Hanford Life Sciences
Symposium. Richland, Wash.: Batelle, Pacific Northwest Laboratory.
16. Cross, F. T., R. L. Buschbom, G. E. Dagle, R. E. Filipy, P. O. Jackson, S. M.
Loscutoff, and R. F. Palmer. 1983. Inhalation hazards to uranium miners. P.
77 in Pacific Northwest Laboratory Annual Report for 1982 to the Department
of Energy Assistant Secretary for Environment, Part 1. PN~4600. Richland,
Wash.: Battelle, Pacific Northwest Laboratory.
17. Cross, F. T., R. L. Buschbom, G. E. Dagle, P. O. Jackson, R. F. Palmer, and
H. A. Dagan. 1984. Inhalation hazards to uranium miners. P. 41 in Pacific
Northwest Laboratory Annual Report for 1983 to the Department of Energy
Assistant Secretary for Environment, Part 1. PNL-5000. Richland, Wash.:
Battelle, Pacific Northwest Laboratory.
OCR for page 444
444
B~LT7I RISKS OF RADON AND OTHER AI~PNA-EMITTERS
Battelle, Pacific Northwest Laboratory.
18. Cross, F. T., R. F. Palmer, G. E. Dagle, R. E. Busch, and R. L. Buschbom.
1984. Influence of radon daughter exposure rate, unattachment fraction, and
disequilibrium on occurrence of lung tumors. Radiat. Prot. Dosimetry 7:381-384.
19. Gray, R. G., J. Lafuma, S. E. Parish, and R. Peto. In press. Radon inhalation
by rats: An examination of the dose-response relationship for induced pulmonary
tumours and of the exposure parameters and cofactors affecting risk. In Proceed-
ings of the 22nd Hanford Life Sciences Symposium. Richland, Wash.: Battelle,
Pacific Northwest Laboratories.
20. Harris, S. J. 1954. Radon levels in mines in New York State. Arch. Ind. Hyg.
Occup. Med. 10:54 60.
21. Jackson, M. L. 1940. The Biological Effects of Inhaled Radon. M.S. Thesis.
Massachusetts Institute of Technology.
22. Jensen, H., and P. Schultser. 1926. Experimental investigations into the internal
radium emanation therapy. I. Emanatorium experiments with rats. Acta Radial.
6:631.
23. Kushneva, V. S. 1959. P. 21 in On the Problem of the Long-Term Effects of Com-
bined Injury to Animals of Silicon Dioxide and Radon. TR-4473. Washington,
D.C.: U.S. Atomic Energy Commission.
24. Little, J. B., R. B. McGandy, and A. R. Kennedy. 1978. Interactions between
polonium-210, cz-radiation, benzota~pyrene, and 0.9 NaC1 solution instillations in
the induction of experimental lung cancer. Cancer Res. 38:1929.
25. Morken, D. A. 1955. Acute toxicity of radon. Arch. Ind. Health 12:435.
26. Morken, D. A. 1973. The biological effects of the radioactive noble gases. P. 469
in Noble Gases, R. Stanley and A. A. Moghi~i, ede. CONF-730915. U.S. Energy
Development and Research Agency, Washington D.C.: National Environmental
Research Center.
27. Morken, D. A. 1973. The biological effects of radon on the lung. In Noble
Gases, R. Stanley and A. A. Moghissi, ede. CONF-730915. U.S. Energy
Development and Research Agency, Washington D.C.: National Environmental
Research Center.
28. Morken, D. A., and J. K. Scott. 1966. Effects on Mice of Continual Exposure
to Radon and Its Decay Products on Dust. University of Rochester Atomic
Energy Project Report UR-669. Springfield, Va.: National Technical Information
Service.
29. Read, J., and J. C. Mottram. 1939. The Tolerance concentration" of radon in
the atmosphere. Br. J. Radial. 12:54.
30. Schlesinger, R. B., and M. Lippman. 1978. Selective particle deposition and
bronchogenic carcinoma. Environ. Res. 15:424.
31. Shapiro, J. 1954. An Evaluation of the Pulmonary Radiation Dosage from
Radon and Its Daughter Products. University of Rochester Atomic Energy
Project UR-298. Rochester, N.Y.: University of Rochester.
32. Shami, S. G., L. A. Thibodeau, A. R. Kennedy, and J. B. Little. 1982.
Proliferative and morphological changes in the pulmonary epithelium of the
Syrian golden hamster during carcinogenesis initiated by 210po a-Radiation.
Cancer Res. 42:1405.
33. Stuart, B. O., R. F. Palmer, R. E. Filipy, and J. Gaven. 1978. Inhaled radon
daughters and uranium ore dust in rodents. In Pacific Northwest Laboratory
Annual Report for 1977 to the Department of Energy Assistant Secretary for
Environment, Part 1. PNL-2500. Richland, Wash.: Battelle, Pacific Northwest
Laboratory.
Representative terms from entire chapter:
exposure rate
