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Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study conducted to good scientific principles.

Data source

Reference
Reference Type:
publication
Title:
The Effect of Calcium Carbonate Dust on Ventilation and Respiratory Gas Exchange in Normal Subjects and in Patients with Asthma and Chronic Bronchitis
Author:
Norris RM & Bishop JM
Year:
1966
Bibliographic source:
Clin. Sci., 30: 103-115

Materials and methods

Study type:
cross sectional study
Endpoint addressed:
respiratory irritation
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The effects if inhaling calcium carbonate dust were studied in 24 healthy subjects, 8 patients with bronchial asthma and 11 patients with chronic bronchitis. The distribution of ventilation was measured by the single breath oxygen test and respiratory gas exchange was studied by sampling expired gas and arterial blood.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium carbonate
EC Number:
207-439-9
EC Name:
Calcium carbonate
Cas Number:
471-34-1
Molecular formula:
CH2O3.Ca
IUPAC Name:
calcium carbonate
Details on test material:
Calcium carbonate dust was given by passing compressed air at 8 L/min through a Wright dust feed mechanism. The dust clouds passed through two settling bottles to trap larger particles and then through a tube and mouthpiece. The dust cloud was highly aggregated and contained about 120,000 particles/mL in the range 0.5-5.0 µ and about 40,000 particles/mL in the range 0.2-0.5 µ.

Method

Type of population:
general
Details on study design:
STUDY POPULATION
There were 24 healthy subjects who had no respiratory symptoms and no evidence of cardiovascular disease or hypertension and whose ages ranged from 20 to 53 years. Smoking habits varied but none smoked within 1 h of the test.
Eight patients with bronchial asthma and eleven patients with chronic bronchitis were also studied.
The asthmatic patients had had discontinuous attacks of wheezing without cough and sputum for at least 2 years but at the time of study were all in complete remission, all but one having a normal forced expiratory spirogram and all but two having a normal distribution of ventilation as measured by the single breath oxygen test.
The patients with chronic bronchitis had had winter cough and sputum for at least 2 years and wheezing, if present, was a minor complaint. None of them was greatly disabled by breathlessness and none had suffered any recent respiratory tract infection. However, most of the patients had spirographic evidence of airway obstruction and all patients had an abnormal distribution of ventilation.

Details on exposure:
EXPOSURE PROCEDURE
The procedure was identical in the normal subjects and in the patients except that anatomical dead space was measured in conjunction with the single breath test in normal subjects only.
Subjects carried out between 6 and 10 single breath tests after which a brachial artery needle or catheter was inserted. Then two 2-min collections of arterial blood and expired air were made for calculations of the alveolar-arterial difference in oxygen tension (A-aD O2) and the ratio of physiological dead space to tidal volume (Vd/Vt).
Calcium carbonate dust was breathed for 10 minutes, 3-5 deep inspirations per minute being taken with breath holding for 5-7 sec.

SAMPLING/ MEASUREMENTS
Expired gas and arterial blood were collected at 5-7, 12-14, 23-25, 40-42 and 60-62 minutes after the end of dust breathing.
Single breath tests were done at 1, 8, 15-18 (2 tests), 26-35 (4 tests) and 43-55 (5 tests) minutes after dust exposure.

In some of the studies acetyl choline was infused through a catheter percutaneously into superior vena cava or right atrium. Each infusion lasted for 6 min at a rate of 2 mg/min, delivered by infusion pump. Each subject received three infusions of acetyl choline, one before and two after dust.

Results and discussion

Results:
NORMAL SUBJECTS
The mean results in 8 of the subjects showed a significant change in the single breath test after dust exposure. The remaining 6 normal subjects showed no significant rise in the single breath test after dust exposure.
No symptoms occurred after breathing the dust and there was no change in the expired volume (Ve), respiratory exchange ratio (R) or partial pressure of CO2 in arterial blood (Pa,CO2). The nitrogen concentration difference became significantly greater in the whole group of normal subjects at 1 and 26-35 min after dust and was greater though not significantly so at 8, 15-18 and 43-55 min.
In the reactors (8 normal subjects), the increase was significant at all time intervals. A-aD O2 was significantly greater at 5-7, 12-14 and 23-25 min after dust but had returned to control levels at 40-42 and 60-62 min in both the group as a whole and in the reactors. There was no significant change in physiological dead space or Vd/Vt in either group. There was a significant fall in anatomical dead space in the whole group 1 min after dust, but not in the group of reactors.

PATIENTS WITH ASTHMA
All of these patients were reactors but none had any symptoms after breathing the dust. There was again no change in Ve, R or Pa,CO2. The nitrogen concentration difference was significantly greater at 1, 8, 15-18, 26-35 and 43-55 min after dust and the change was of a similar magnitude to that in the normal reactors and from a similar control level. The rise in A-aD O2 was no greater than in the normal reactors but the return of A-aD O2 to control levels was slower, there being a significant increase in A-aD O2 at 40-42 min after dust. Vd/Vt decreased after dust but this change was not significant.

PATIENTS WITH CHRONIC BRONCHITIS
6 of these 8 patients proved to be reactors but none of them had symptoms after breathing dust. The nitrogen concentration difference was significantly raised at 1, 8, 15-18 and 26-35 min and if the 2 non-reacting patients are excluded, the increase was also significant at 43-45 min. A-aD O2 was raised at 5-7, 12-14, 23-25 and 40-42 min after dust; the 40-42 min increase being insignificant in the whole group but significant in the 6 reactors. There was no change in physiological dead space or Vd/Vt. Thus the bronchitic reactors showed a similar decline of A-aD O2 with time to that found in the patients with asthma and this was slower in the normal subjects. The increase in N2 concentration difference was greater in the bronchitics but the initial control value was abnormally large while the increase in A-aD O2 was smaller than normal from an abnormally high control level.

INFUSIONS OF ACETYL CHOLINE BEFORE AND AFTER DUST
Acetyl choline infused into the right atrium caused a small increase in A-aD O2 in the control state. On 3 occasions the infusion was repeated at a time after dust exposure when the A-aD O2 had returned to normal but the single breath test remained abnormal; there was then a greater increase in A-aD O2.

Applicant's summary and conclusion

Conclusions:
1). Alveolar ventilation was distributed more unevenly as indicated by a significant increase in the slope of the single breath test, after breathing dust in ten of the normal subjects all of the patients with asthma and 8 of the patients with chronic bronchitis. This increase persisted for 43-55 min.
2). In normal subjects the A-aD O2 increased after breathing dust and remained elevated for 23-25 min. There was no significant change in physiological dead space and only a small transient decrease in anatomical dead space.
3). The patients with asthma showed a change in the single breath test which was similar to the normal subjects but the increase in A-aD O2 was more protracted.
4). It was difficult to compare the ventilatory changes in the patients with chronic bronchitis since the initial slope of the single breath test was greater than normal. The time course of the increase in A-aD O2 was similar to that in the patients with asthma.

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