Chromate Lung Cancer with Special Reference to its Cell Type and Relation to the Manufacturing Process

SHOSAKU ABE, MD, YUTAKA OHSAKI, MD, KIYONOBU KIMURA, MD, YASUHIRO TSUNETA, MD, HlROSHl MIKAMI, MD. AND MAKOTO MURAO, MD

The manufacturing process of the chromate industry can be classified into five steps. The main hazardous pollutants of the first step are trivalent chromate compounds, and those of the second and third steps are hexavalent chromate compounds. Analysis of the detailed working history of chromate workers with bronchogenic carcinoma, yielded the following results: the work history of chromate lung cancer patients in the first step, which produced mainly trivalent chromate dust, was rather short. Patients with small cell carcinoma were engaged mainly in the second step (98.1% of the total working months), where they were heavily exposed to hexavalent chromate dusts. Patients with squamous cell carcinoma were engaged rather evenly in the second and fourth steps, and somewhat longer in the third step. Comparisons o f the exposure periods revealed that the working history of small cell carcinoma patients was significantly shorter than that of squamous cell carcinoma patients. There were many more heavy smokers among the squamous cell carcinoma group as compared to the small cell carcinoma patients. Based on these results, it i s concluded that the cell type of occupational lung cancer was mainly small cell carcinoma when the exposure to carcinogenic agents was heavy, and that the carcinogenicity of chromate was derived mainly from hexavalent chromate rather than trivalent compounds.

Cancer 49:783-787. 1982.

O M E COMPOUNDS of chromium display harmful S effects including ulceration of the skin, perfora- tion of the nasal septum, bronchogenic carcinoma, etc. The first case of bronchogenic carcinoma among chro- mate workers was reported in Germany by Pfeil,4 fol- lowed by similar cases in the United States and En- gland.'.' I n Japan, the first study on bronchogenic carcinoma in the chromate industry was performed by Ohsaki et u I . ~ From the cumulative data, cancer of the respiratory tract among the workers is believed to rep- resent one of the occupational diseases.

Occupational lung cancer is known to be affected by the type of inhaled carcinogens, the exposure period, and the amount of such substances. However, full de- tails of the carcinogenicity of chromium compounds in relation to soluble hexavalent and insoluble trivalent chromate remain to be elucidated. Several steps make up the manufacturing process of the chromium indus- try, and the production of soluble and insoluble chro- mate is related to certain types of these manufacturing processes.

I n the present study, we investigated the detailed work history of chromate lung cancer patients and as-

~

From the First Department of Medicine, Faculty Medicine, Hok-

Accepted for publication January 5, 1981. kaido University, North 14, West 5, Sapporo, Japan.

sessed the relation between the occurrence of broncho- genic carcinoma and the type of exposed chromate.

Subjects and Methods

The subjects comprised 20 cases of bronchogenic car- cinoma whom we encountered among chromate work- ers. All were male, ranging in age from 26-74 years (average, 50.5 years). All but five cases were heavy smokers. The histologic type of cancer was squamous cell carcinoma in 13 cases and small cell carcinoma in five cases. The remaining two cases were not defined, due to lack of precise information. Perforation of the nasal septum was observed in 13 cases.

The work period of the chromate workers expressed i n months and individual working periods were added. The period of exposure to chromate dust or mist was found to range from 64-342 months (average, 260.9 months). The main products of the factory concerned were chromic acid, sodium dichromate, and potassium dichromate. According to the working process, we clas- sified the manufacturing process into five steps (Fig. 1). The first step is the combination of chrome ore (FeO- Cr203) with sodium carbonate and caustic lime. During this process, trivalent insoluble chromate dust is pro- duced. The second process is the drying up of the pre- viously combined product in a rotary kiln, followed by

OoO8-543X/82/02 I5/0783 $0.75 Q American Cancer Society

783

784 CANCER February I S 1982 VOl. 49

Combination, Crush

J. I Percolation Na2CrOs I

i+ H2SOc

Evaporation Na2Cr207*2H20

Electric furnaces, brickmaking

Subcontractors Laboratory workers

I Off ice workers I FIG. I . Manufacturing process of the chromate producing factory.

percolation with water, producing sodium monochro- mate (Na2Cr0,). The third step produces sodium di- chromate (Na2Cr207 e 2H20) by the addition of sulfuric acid. During the second and third steps, soluble hex- avalent chromate is produced. The fourth step includes the work process of treatment of the final product, at which point there is relatively little chromate dust in the work place. Brickmaking, mechanical and labora- tory workers, as well as office workers, are involved in the fifth step, which is not in a dusty work area.

Based on the detailed work history of the subjects, we investigated the relationship between the occurrence of bronchogenic carcinoma and the particular manu-

facturing processes in which the patients were engaged. As the control group, members of the workforce with and without nasal perforation (55 and 52 persons, re- spectively) were selected, and their work histories were matched with the cancer patients.

Results

Work Period in Relation to Steps of the Manufacturing Process (Table 1)

Among the subjects with bronchogenic carcinoma, of whom the total combined work period amounted to 5,219 months, the duration of the first step accounted for 380 months (7.3%), and those of the second and third steps for 1,211 months (23.2%) and 2,116 months (40.5%), respectively. The corresponding figures for the control group with nasal perforation were 1,702 months (14.4%) in the first step, 880 months (7.5%) in the sec- ond, and 1,290 months (10.9%) in the third step.

The control group without nasal perforation revealed even smaller work periods in the second and third steps, i.e., 6.1 and 8.7%, respectively, compared to the other groups. These results clearly demonstrate that the can- cer patients were engaged in the second and third steps for significantly longer periods than the noncarcinoma workers.

Cell Type of Bronchogenic Carcinoma in Relation to Steps of the Manufacturing Process (Table 2)

Similar data to the above were compiled for the bron- chogenic carcinoma patients based on the classification of their cell type. Thirteen patients with squamous cell carcinoma were engaged in the first process for 380 months (9.6% of the total combined work period), in the second process for 592 months (1 5.2%), and in the third process for 1,609 months (41.2%). On the other hand, five patients with small cell carcinoma were en- gaged mainly in the second process for a total of 619 months (98.1%). Thus, having their work place con- centrated in the second step, the total exposure period to chromate dust in the small cell carcinoma patients

TABLE 1. Total Exposure Period and its Division Among the Steps of the Manufacturing Process

Total exposure Exposure period by step of the manufacturing Age range period in process, (months) (% of total period)

Number of (years) months subjects (Mean f S.D.) (Mean f S.D.) I I 1 111 1v V

Carcinoma 20 26 - 74 5219 380 I21 1 21 16 832 680 (50.5 f 10.7) (260.9 f 102.8) (7.3) (23.2) (40.5) (15.9) (13.1)

Noncarcinoma with 55 35 - 81 11786 I702 880 1290 6060 1854 nasal perforation (53.3 & 12.1) (214.3 f 111.2) (14.4) (7.5) (10.9) (51.4) (15.8)

Noncarcinoma without 52 34 - 79 10992 2692 679 956 2582 408 3 nasal perforation (54.6 f 11.3) (211.4 f 101.9) (24.5) (6.1) (8.7) (23.5) (37.2)

No. 4 CHROMATE LUNG CANCER . Abe et al. 785

TABLE 2. Cell Type of Chromate Lung Cancer and Exposure Period at Different Steps of the Manufacturing Process

Total exposure Exposure period by step of the manufacturing process, Age range period in (months) (96 of total pexiod)

Number of (years) months subjects (Mean f S.D.) (Mean f S.D.) I I1 111 IV V

Carcinoma 20 26 - 74 5219 380 121 1 2116 832 680

Squamous cell 13 38 - 74 3907 380 592 1609 760 566

(50.5 f 10.7) (260.9 f 102.8) (7.3) (23.2) (40.5) (15.9) (13.1)

carcinoma (51.5 f 9.5) (300.5 f 69.5) (9.6) (15.2) (41.2) (19.5) (14.5)

Small cell carcinoma 5 26 - 67 63 1 0 619 12 0 0 (48.8 f 15.3) (126.2 f 62.9) (98.1) (1.9)

Cell type unknown 2 40 - 56 68 1 0 0 495 72 114 (47.0 f 11.3) (340.5 f 57.3) (72.7) (10.6) (16.7)

was significantly shorter than that in the squamous cell carcinoma patients. There was a relatively short or no history of engagement in the first step in the carcinoma patients, indicating that trivalent chromate dust was not primarily related to the induction of bronchogenic carcinoma.

Cell Type of Bronchogenic Carcinoma and Exposure Period to Chromate Dust

Comparisons between the age at which exposure to chromate dust began and the cell type, revealed that the age of initial chromate exposure was significantly younger in squamous cell carcinoma patients than in small cell carcinoma patients; i.e., the age of initial exposure to chromate dust was from 15-31 years (av- erage, 24.0 f 4.3) in squamous cell carcinoma patients and from 17-51 years (average, 34.4 -t 13.4) in small cell carcinoma patients (Fig. 2). The age of lung cancer occurrence was from age 38-74 years (average, 51.5 -+ 9.5 years) in squamous cell carcinoma patients, and from age 26-67 years old (average, 48.4 -t 15.3 years) in small cell carcinoma patients. There was no signif- icant difference between these values (Fig. 3). The above results therefore indicate that the latent period (total exposure period between initial exposure and oc- currence of lung cancer) was significantly longer in squamous cell carcinoma patients, from 167-499 months (average, 344.4 f 92.5 months), than in small cell car- cinoma patients, from 100-268 months (average, 173.4 f 63.9 months) (Fig. 4).

induction. The occurrence of small cell carcinoma was apparently not so significantly influenced by the smok- ing habit as that of squamous cell carcinoma.

Discussion

Following the first report in Germany' and then those in the United States and the carcinogenicity of chromate compounds had become clear. However, some dispute exists as to which of trivalent and hex- avalent chromate compounds has carcinogenicity. Man- cuso and Hueper6 incriminated insoluble chromium, such as chromic dust and chromic oxide, as a carci-

Age (yrs> :'i 40

0

o T

O ! 0

20 301 a 0 P 0

'"1 Smoking History of the Carcinoma Patients (Fig. 5 )

Smoking histories revealed that squamous cell car- cinoma patients smoked more heavily than small cell carcinoma patients. This indicated that squamous cell carcinoma of the chromate workers was strongly influ- enced by the smoking habit, which could represent one of the accelerating factors in bronchogenic carcinoma

I Squamous small' cell carcinoma cell carcinoma Number : 13

LN.S.A Number : 5

FIG. 2. Relationship between age of initial exposure to chromate and cell type of chromate lung cancer.

786

60-

50 =

40 - 30

20 - 1 0 -

CANCER February 15 1982 Vol. 49

70 * O l 0

3 “p 0

0

0 0

0 - 1 0

0

I Squamous Small cell carcinoma cell carcinoma Number : 13 I N . S . 1

Number : 5

FIG. 3. Relationship between age of onset and cell type of chromate lung cancer.

nogenic substance. Machel and Gregorious’ pointed out that monochromate was a carcinogenic substance since many lung cancer patients were detected in a factory which handled monochromate only, as compared to a relatively low incidence of lung cancer in a factory han- dling dichromate.

In the manufacturing process, it is clear that trivalent and hexavalent chromium compounds are produced. In the first step, the main products are trivalent and water insoluble chromium compounds. In the second and third steps, mono- or dichromate with hexavalency and water solubility is mainly produced.

Our investigation revealed that the bronchogenic car- cinoma patients encountered in the chromate industry were engaged in the manufacturing process where hex- avalent chromate dust was produced, for a longer period (63.7% of the total working months) than in the tri- valent producing working place (7.3% of the total work period). The small cell carcinoma group revealed that almost all work was in the second step in the hexavalent producing place (98.1 % of the total working period), and no cancer patients were engaged in the first, tri- valent producing area. On the other hand, in noncancer controls with nasal perforation, the work period in the

second and third steps amounted to only 18.4% of the total months, while the corresponding figure for the controls without nasal perforation was 14.8% of the to- tal work period. These findings are consistent with the report of Machel and Gregorious,’ indicating that bron- chogenic carcinoma occurred exclusively in workers engaged in work in a hexavalent chromate compound producing place. From the viewpoint of carcinogenicity, hexavalent chromate compounds are thus apparently more important than trivalent chromate compounds. Levis and Majone’ confirmed that hexavalent chromate compounds were markedly cytotoxic and clastogenic in mammalian cell cultures when compared to soluble tri- valent chromate compounds. Soluble hexavalent chro- mate is readily changed to insoluble trivalent com- pounds by oxide-reductive reactions, such as with ascorbic acid. Inhaled hexavalent compounds are said to be retained for long periods in the state of trivalent compounds in the body by a reduction process. Previ- ously, we reported the chromium content in extirpated and autopsied lungs of chromate lung cancer patients.

500

‘Z 400< 5 C z W

300 .- I a, tl

t

rn -I

-w

E 200

1001

0

0

0

80 0. 0.

0

0 0

0

I 8

Squamous Small cell carcinoma cell carcinoma Number : 13 Number : 5

L-P<O.Ol I FIG. 4. Relationship between latent period and cell type of chromate

lung cancer.

No. 4 CHROMATE LUNG CANCER . Abe el al. 787

Our results demonstrated high contents of chromium in the upper lungs. The primary site of bronchogenic carcinoma, however, is located exclusively in the major airway of the hilar area, not in the lung periphery; i.e., a high local content of chromium is not necessarily a condition for the induction of bronchogenic carcinoma.' The period from initial exposure to the occurrence of lung cancer averaged 288 k 1 11.2 months, which the same as Hueper's' figure of 24 years.

Saccomanno et al.' reported a high incidence of small cell carcinoma among uranium miners who were ex- posed to increasing radiation. In our study, pollution of chromium dust may be heaviest in the second step of the manufacturing process. The present results and Saccomanno's report thus suggest that the heavier the exposure to the occupational carcinogen, the higher the incidence of small cell carcinoma tends to be. Saccom- anno's report also stated that an average of 15.9 years elapsed from the beginning of mining to the develop- ment of cancer. This number of years is quite similar to our result for small cell carcinoma patients, where the duration from the initial exposure to chromate dust to the development and confirmation of bronchogenic carcinoma was 180 months. When exposure to a car- cinogen is not of heavy but long duration, squamous cell carcinoma might become the predominant cell type of occupational cancer, and was apparently accelerated due to smoking in our cases.

Summary

The relationship between the steps of the manufac- turing process of the chromate industry and the occur- rence of bronchogenic carcinoma was investigated. Chromate workers with small cell carcinoma were en- gaged mainly in the second of the five steps, indicating that they worked an environment heavily polluted with hexavalent chromate dust. Subjects with squamous cell carcinoma were engaged in the second, third and fourth steps. The latent period (the period between the initial exposure to chromate dust and detection of broncho- genic carcinoma) was shorter in the small cell carci- noma group than in the squamous cell carcinoma group, suggesting that exposure to heavily concentrated chro- mate dust could induce small cell carcinoma, as in the case of other carcinogens. The carcinogenicity of chro- mate compounds may not reside in the trivalent ma- terials, since the carcinoma patients were engaged for

Pack years I .

4 0 1 i I 30

I *. I '"1 1 'O1

I

L - Squamous Small cell carcinoma cell carcinoma Number : 13 Number: 5

-N.S. I FIG. 5. Relationship between smoking history and cell type of chro-

mate lung cancer.

only comparatively short periods in the first step of the manufacturing process where trivalent chromate dust represented the main pollutant.

REFERENCES

1 . Hueper WC. Occupational and environmental cancers of the respiratory system. New York: Springer-Verlag, 1966.

2. William W, Robert LM, Oscar A. Lung cancer in chloromethyl either workers. Am Rev Respir Dis 1979; 120:1031-1037.

3. Ohsaki Y, Abe S , Kimura K, Tsuneta Y, Mikami H, Murao M. Lung cancer in Japanese chromate workers. Thorax 1978; 33:372- 374.

4. Pfeil E. Lungentumoren also berufserkrankung in chromatbe- trieben. Deutsch medizinische Wochenschrifi 1935; 61: I 197-1200.

5. Machel W, Gregorious F. Cancer of the respiratory system in the United States chromate-producing industry. Public Health Rep

6. Mancuso TF, Hueper WC. Occupational cancer and other health hazards in chromate plant. A medical appraisal. Industrial Med Surg 1951; 20:358-363.

7. Tsuneta Y, Ohsaki Y, Kimura K, Mikami H, Abe S. Murao M. Chromium content of lungs of chromate workers with lung cancer. Thorax 1980; 35:294-297.

8. Saccomanno G, Archer VE, Oscar A, Kuschner M, Saunders RP, Klein MG. Histologic type of lung cancer among uranium miners. Cancer 1971; 27513-523.

9. Levis AG, Majone F. Cytotoxic and clastogenic effects of soluble chromium compounds on mammalian cell cultures. Br J Cancer 1979;

1948; 63~1114- I 1 27.

401523-533.