Acute promyelocytic leukemia

ACUTE MYELOID LEUKEMIA (AML) may be caused by environmental exposure to benzene[1] and ionizing radiation.[2] There is "limited evidence" for a causal association between exposure to ethylene oxide in combination with other chemicals and AML in man.[3] Some studies have reported a possible link between exposure to electromagnetic fields and AML.[4]

We used the Swedish Cancer Environment Register (CER) to generate hypotheses on unknown environmental etiologies of AML and to identify occupations with a previously unknown increased risk of AML.

Materials and methods

The study population included gainfully employed Swedes who were between the ages of 20 and 64 y in 1970 (n = 3 308 444). In the 1970 census, the information obtained from each individual regarding occupation during the week of October 4-10 was coded according to a slightly modified Nordic Occupational Classification Scheme. The number of occupations was 295. Through the unique 10-digit identification number assigned to every Swedish resident, the census information was linked to the information on incident cancer cases in the National Swedish Cancer Register during the period 1971-1984, in order to create the CER-70.[5,6] There were 1 275 cases of AML (ICD code 204.6 for 1971 to 1974 and ICD code 205.0 for 1975 and onwards).

The observed number of AML cases within an occupation was compared with the expected number calculated by multiplying the AML incidence rates in the entire study population, with stratification for age (5-y classes), county (n = 24), degree of urbanization (2 levels), and calender year, with the numbers of person-years in the occupation under study, and by summarizing over all strata. Expected numbers were calculated separately for men and women. Exact 95% confidence intervals (CI) were calculated for the ratio between observed and expected numbers, based on the Poisson distribution.

Surviving relatives of cases in the occupational groups who showed an elevated risk of AML (lower bound of 95% CI at least 1.0, and based on at least five cases in one sex) were mailed a questionnaire on the work history of the deceased relative. One week later they were interviewed, by telephone, by an industrial hygienist (RJ). Copies of the hospital records of each patient were procured from the clinics where the diagnoses were made.

Results

The only occupational group that showed a significantly elevated risk of AML was male "petrol station attendants and demonstrators" (approximately 9 000 men in the 1970 census with occupational code 338). Ten cases of AML occurred versus 2.8 expected, yielding an observed/expected ratio of 3.6 (95% CI 1.7-6.6). No occupational group showed a significantly decreased risk.

A reasonable hypothesis was that exposure to benzene from petrol had contributed to the excess risk of AML, given that petrol in Sweden has contained up to 5% of benzene for several decades. This hypothesis could have been refuted by showing that a large proportion of the 10 cases had not been more exposed to petrol than the Swedish male population in general. Work histories of all 10 cases, now deceased, could be obtained through interviews with wifes and in two cases, parents or children.

Case reports

Case 1 (born 1923 in Finland). Between 1946 and 1956, he worked in grocery stores in the Finnish countryside. The shops also had petrol pumps, and the employees filled the customers' cars. Between 1958 and 1961, he was a rubber manufacturing worker in Canada, where benzene exposure could have occurred. From 1961 until 1982, he worked for a large, car manufacturing company in Sweden, and he demonstrated new cars. AML was diagnosed in 1982, and the patient died with this diagnosis the same year.

Case 2 (born in 1929). During the 1950s, he sold spare equipment for cars and worked as a taxi driver. During some years in the 1960s, he worked with finishing and anti-corrosive treatment of new automobiles. Work-related exposure to petrol seems to have occurred only between 1%7 and 1971, when he worked as a petrol station attendant refuelling the customers' cars. From 1971 until 1986, he once again worked with finishing and anti-corrosive treatment of automobiles. Given his great interest in motors, exposure to petrol occurred also during leisure time. Aplastic anemia and AML were were diagnosed in 1983, and the patient died with the latter diagnosis in 1987.

Case 3 (born in 1930). Between 1944 and 1953, he was employed as gardener, mechanical worker, and lorry driver. From 1953 until 1974, he worked as a petrol station attendant filling up the customers' cars. Between 1974 and 1984, he was a mechanical worker. AML was diagnosed in 1984, and the patient died from this diagnosis in 1985.

Case 4 (born in 1924). He worked as a sailor and marine engine mechanic worker on cargo ships in the Baltic Sea and the North Sea between 1941 and 1956. Between 1956 and 1976, he worked as a captain on refuelling ships, filling up diesel oils and light fuel oils in other ships in a Swedish harbour. Thus, work-related exposure to petrol seems not to have occurred. AML was diagnosed in 1978, and the patient died from this diagnosis in 1979.

Case 5 (born in 1925). Immediately after school, he worked as an agricultural worker, and from 1943 to 1945 he was employed as a lorry driver. Between 1946 and 1951 and from 1954 to 1979, he worked as a petrol station attendant. The pumps were operated by the attendants until the end of the sixties. One pump was operated by the attendants, even until 1979. AML was diagnosed in 1979, and he died the same year from the diagnosis leukemia.

Case 6 (born in 1928). This individual worked as a clerk between 1945 and 1965. In 1965 he became a selling consultant for a petrol company. Between 1967 and 1969, he worked as a petrol station attendant refuelling the customers' cars. From 1969 to 1978, he trained petrol station attendants, and this work may have also involved some petrol exposure. AML was diagnosed in 1978, and he died from the diagnosis acute leukemia in 1979.

Case 7 (born in 1925). He worked as a farmer until 1965, and from 1965 to 1974 he was employed as a serviceman at a large airport. His main duty was to refuel big air liners. Accordingly, he was exposed to aviation petrol and kerosene, but not to conventional petrol. AML was diagnosed in 1974, and he died the same year from this diagnosis.

Case 8 (born in 1940). He worked in a food-processing plant between 1956 and 1958. Between 1958 and 1976, he worked as a petrol station attendant. Until the late 1960s, he filled up the customers' cars. He also worked with anti-corrosive treatment of automobiles during this period. AML was diagnosed in 1976, and he died from this diagnosis in 1977.

Case 9 (born in 1950). Between 1965 and 1974, he was employed as a petrol station attendant refuelling the customers' cars. Between 1974 and 1978, he worked at a self-service station. AML was diagnosed in 1978, and he died from this diagnosis in 1981.

Case 10 (born in 1950). Between 1965 and 1967, he was trained as a motor mechanic in a vocational school. From 1967 until 1969, he worked as a petrol station attendant filling up the customers' cars. During 1969 and 1970 he did military service. Between 1970 and 1974, he was employed in a mechanical workshop. His hobby was motors, which probably involved some petrol exposure. AML was diagnosed in 1974, and he died from this diagnosis in 1976.

Summary of case reports

The petrol and benzene exposure of the 10 cases is summarized in Figure 1. The hospital records showed that all AML diagnoses were made by pathologists subsequent to bone marrow biopsy. We did not scrutinize the remaining slides, but a simple miscoding of AML in the cancer register seems excluded. All the cases probably suffered from AML or related disorders.

Discussion

The discussion addresses three issues: (1) the causal association between exposure to petrol and leukemia, (2) the exposure level to benzene at the petrol stations, and (3) the exposure-response relation between benzene exposure and leukemia.

Is there an increased risk for AML among the petrol station attendants?

In the entire group of "petrol station attendants, demonstrators, etc" in the 1970 census, the petrol station attendants amounted to 95% (Hagerlund J, Statistics Sweden, personal communication). Six of the cases were petrol station attendants at the time of the 1970 census, and one more individual (case 10) was an attendant during a period that was close to the time of census. Case I had worked previously as a petrol station attendant and had also worked in a rubber industry, which could have involved exposure to benzene. Case 7 refuelled airplanes with aviation petrol or aviation kerosene, which contain < 1%, and < 0.02% benzene, respectively (Jersin R, Swedish British Petroleum, personal communication). Case 4 was occupationally exposed to diesel oil and light fuel oils that contained very low levels of benzene, i.e., < .05%.[7]

The time from the first employment as petrol station attendant until diagnosis varied from 9 to 36 y (median = 16 y), which is similar to the time from first exposure to benzene until the diagnosis of AML reported in the literature: 3.5 to 37 [y.sup.8] and from 0.8 to 50 y (median = 11.4 y).[9]

Two Swedish case-referent studies indicated a significant association between petrol exposure and AML.[10,11] In a Proportionate Mortality Ratio (PMR) study performed in the United States, an increased risk for leukemia, including AML, was found among workers in car service stations.[12] Some recently published case reports have strengthened the suspicion of a causal association between petrol exposure and leukemia (principally AML).[13,14] A recent Danish mortality study among petrol station attendants did not find an excess of leukemia.[15] Quantitative estimates of petrol or benzene exposure were not reported in any of these studies.

Therefore, our data accord with the hypothesis that work as a petrol station attendant involves an increased risk of AML. Because petrol contains benzene, and the times from first exposure to diagnosis are in keeping with benzene-induced AML, it appears possible that benzene exposure may contribute to this risk.

Exposure to benzene in petrol stations

Petrol is specified to meet certain technical standards and has no defined composition but, rather, is dependent on the crude oils and the refinery processes. Since the 1950s, the average benzene content in petrol varied between 3 and 5% (Jersin R, Swedish British Petroleum, personal communication).

During the process of filling 30 1 of petrol containing 5% benzene in a car, about 700 mg benzene is released.[16] The emission of benzene from exhausts when idling is approximately 10 mg/min for a car that is not equipped with a catalytic converter (Laveskog A, Swedish Car Testing Ltd, personal communication).

Until around 1970, most Swedish petrol station attendants operated the petrol pumps. The benzene exposure at such work has been studied in several countries (Table 1).

[TABULAR DATA OMITTED]

The petrol in the United States has a lower content of benzene (approximately 0.8%) than what is common in Europe (up to 5%).[1] However, this difference is not reflected in the measured air levels, perhaps the result of differences in other factors that heavily influence benzene exposure, such as filling frequency, temperature, wind conditions, and work practices.[22] Airborne exposure to benzene among Swedish petrol station attendants was probably low, compared to previously studied industrial exposures (e.g., in the rubber industry[8]), also prior to the introduction of self-service stations.

The handling of petrol during previous decades was probably less careful than today. It has been reported to us that many workers used petrol for cleaning their hands from oil and grease. Animal experiments suggest that frequent exposures of the hands may yield a percutaneous absorption of benzene of the same magnitude as lung uptake from a benzene air level in the order of 1 mg/ [m.sup.3].[23]

Exposure-response relationships in an epidemiological

study

Leukemia mortality has been investigated among benzene-exposed men employed in a rubber plant in the United States. Nine cases of leukemia, of which at least 7 were AML, were observed, compared to 2.7 expected. An increase in cumulative benzene exposure from < 130 Mg/ [m.sup.3]-y (< 40 ppm-y) to 130-640 mg/ [m.sup.3]-y (40-199 ppm-y) corresponded to an increase in the observed/expected ratio from 1.1 to 3.28. Therefore, the lowest benzene air levels that have been associated with an increased risk of AML are considerably higher than the levels measured at petrol stations (Table 1).

Conclusions

Men reported as "petrol station attendants and demonstrators" in the Swedish census of 1970 show an excess risk of AML. Exposure to benzene from petrol has most likely contributed to the excess risk.

The average air levels of benzene at petrol stations were lower than the levels previously reported to yield an increased risk of leukemia in epidemiological studies. It appears unlikely that the excess risk of AML may be explained by airway benzene exposure only, although previous studies may have underestimated the risk. Contributing causes may be skin uptake of benzene or that other components in petrol and/or exhausts from vehicles add to, or potentiate, the leukaemogenic effect from benzene.

Swedish "petrol station attendants" now have a lower petrol exposure because of the development toward self-service stations. However, attendant-served stations still predominate in many countries. The introduction of vapor recovery systems in petrol stations will further decrease the petrol exposure among the attendants, but other occupational groups, such as tank lorry drivers and motor mechanics, will also probably experience considerable exposure in the future. Moreover, large parts of the general population have a low exposure to petrol vapour during the self-fuelling process of their private car. We believe it important to continue the decrease of exposure to petrol vapor in general, to characterize more closely the chemical exposures in petrol distribution and handling, and to further examine the exposure-response relationship between such exposures and leukemia.

References

[1.] International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks of chemicals to humans. Some industrial chemicals and dyestuffs; vol 29. Lyon: IARC, 1982; pp. 93-148. [2.] United Nations. United Nations Scientific Committee on the Effects of Atomic Radiation. UN Publication No E77.1x.1. New York: United Nation, 1977; pp. 370-77. [3.] International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks of chemicals to humans. Allyl compounds, aldehydes, epoxides and peroxides; vol 36. Lyon: IARC, 1985; pp. 189-226. [4.] Savitz DA, Calle EE. Leukemia and occupational exposure to electromagnetic fields: review of epidemiological surveys. J Occup Med 1987; 29:47-51. [5.] Wiklund K, Einhorn J, Wennstrom G. A Swedish Cancer-Environment Register available for research. Scand J Work Environ Health 1981; 7:64-67 [6.] National Board of Health and Welfare. Cancer-miljoregistret-70. (Cancer Environment Register 70). SOS-rapport 1989:19. Stockholm: Allmanna forlaget AB, 1989. (In Swedish). [7.] International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Occupational exposures in petroleum refining: crude oil and major petroleum fuels; vol 45. Lyon: IARC, 1989. [8.] Rinsky A, Smith AB, Hornung R, et al. Benzene and leukemia. An epidemiologic risk assessment. N Engl J Med 1987; 316:1044-50. [9.] Yin S-N, Li G-L, Tain F-D, et al. Leukaemia in benzene workers: a retrospective cohort study. Br J Ind Med 1987; 44:124-28. [10.] Flodin U, Fredriksson M, Axelson O, Persson B, Hardell L. Background radiation, electrical work, and some other exposures associated with acute myeloid leukemia in a case-referent study. Arch Environ Health 1986; 41:77-84. [11.] Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute non-lymphocytic leukaemia. Br Med J 1978; 4:553. [12.] Schwartz E. Proportionate mortality ratio analysis of automobile mechanics and gasoline service station workers in New Hampshire. Am J Ind Med 1987; 12:91-99. [13.] Infante PF, Schwartz E, Cahill R. Benzene in petrol: a continuing hazard. Lancet 1990; 336:814-15. [14.] Lumley M, Barker H, Murray JA. Benzene in petrol. Lancet 1990; 336:1318-19. [15.] Grandjean P, Andersen O. Lung cancer in filling station attendants. Am J Ind Med 1991; 20:763-68. [16.] Runion H. Benzene in gasoline. Am Ind Hyg Assoc J 1975; 36:338-50. [17.] CONCAWE. The oil companies' international study group for conservation of clean air and water. A survey of exposure to gasoline vapour. Report No 4/87. The Hague, CONCAWE, 1987. [18.] Parkinson GS. Benzene in motor gasoline - an investigation into possible health hazards in and around filling stations and in normal transport operations. Ann Occup Hyg 1971; 14:145-53. [19.] Rappaport S M, Selvin S, Waters M A. Exposures to hydrocarbons components of gasoline in the petroleum industry. Appl Ind Hyg 1987; 2:148-54. [20.] McDermott HJ, Voss GA. Service station attendants' exposure to benzene and gasoline vapors. Am Ind Hyg Assoc J 1979; 40:315-21. [21.] Halder CA, Van Gorp GS, Hatoum NS, Warne TM. Gasoline vapour exposures. Part 1. Characterization of workplace exposures. Am Ind Hyg Assoc J 1986; 47:164-72. [22.] Nordlinder R, Ljungkvist G. Bensen och totalviteexponering vid tankning av personbilar. (Exposure to benzene and total hydrocarbons at car refueling). Rapport fran Kemikalienspektionen 2/89. Solna: Kemikalieninspektionen, 1989. [23.] Susten AS, Dames BL, Burg JR, Niemeier RW. Percutaneous penetration of benzene in hairless mice: an estimate of dermal absorption during tire-building operations. Am J Ind Med 1985; 7:323-35.

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