Environmental Health Perspectives

Vol. 82, pp. 193-197, 1989

Hematotoxicity and Carcinogenicity of

Benzene

by Muzaffer Aksoy*

The hematotoxicity of benzene exposure has been well known for a century. Benzene causes leukocytopenia,

thrombocytopenia, pancytopenia, etc. The clinical and hematologic picture of aplastic anemia resulting from

benzene exposure is not different from classical aplastic anemia; in some cases, mild bilirubinemia, changes

in osmotic fragility, increase in lactic dehydrogenase and fecal urobilinogen, and occasionally some neurological abnormalities are found. Electromicroscopic findings in some cases of aplastic anemia with benzene

exposure were similar to those observed by light microscopy. Benzene hepatitis-aplastic anemia syndrome

was observed in a technician with benzene exposure. Ten months after occurrence of hepatitis B, a severe

aplastic anemia developed. The first epidemiologic study proving the leukemogenicity of benzene was performed between 1967 and 1973 to 1974 among shoe workers in Istanbul. The incidence of leukemia was 13.59

per 100,000, which is a significant inorease over that of leukemia in the general population. Following the

prohibition and discontinuation of the use of benzene in Istanbul, there was a striking decrease in the number of leukemic shoe workers in Istanbul. In 23.7% of our series, consisting of 59 leukemic patients with benzene exposure, there was a preceding pancytopenic period. Furthermore, a familial connection was found

in 10.2% of them. The 89.8% of our series showed the findings of acute leukemia. The possible factors that

may determine the types of leukemia in benzene toxicity are discussed. The possible role of benzene exposure

is presented in the development of malignant lymphoma, multiple myeloma, and lung cancer.

Introduction

The hematotoxicity of chronic benzene poisoning has

been well known for nearly a century. The effects of benzene include leukocytopenia, thrombocytopenia, anemia,

transitory leukocytosis, lymphopenia, rarely lymphocytosis, very rarely pseudo-Pelger Huet anomaly changes

in the leukocyte osmotic resistance, decreased phagocytic

function of granulocytes, reduced glucogen content and

inhibited activity of peroxidase of neutrophils, an increase

in the acid phosphatase and P-glucoronidase activity of

the neutrophils, and a decrease of alkaline phosphatase,

myeloperoxidase and lipid content of the neutrophils (1).

In addition, in chronic benzene toxicity a decrease of the

Ea and E18 rosetts (T cells) was noted (1). Furthermore,

an increase of leukoagglutinins was demonstrated in the

sera of some workers exposed chronically to benzene. (1).

An increase of eosinophils, basophils, and monocytes in

chronic benzene toxicity is a matter of discussion (1). This

problem, particularly concerning monocytes, deserves

further investigation with modern techniques. In chronic

benzene toxicity, some other qualitative abnormalities,

such as the presence of giant platelets, has been found (1).

*The Scientific and Technical Research Council of Turkey, Research

Institute for Basic Sciences, Department of Biology, Gebze, Kocaeli,

Tur key.

According to Craveri, the hemorrhagic effects of chronic

benzene toxicity are not solely due to thrombocytopenia

but are also due to increased fibrinolytic activity (2).

Aplastic Anemia or Pancytopenia

Resulting from Chronic Benzene

Exposure

The clinical and hematologic picture of benzene-induced

aplastic anemia which is characterized by pancytopenia,

is not different from that of classical aplastic anemia idiopathic or because of different chemicals or other agents

(1). In some cases of benzene-induced aplastic anemia,

there are characteristics that are absent when this

hematologic disorder is caused by other agents, such as

mild bilirubinemia, changes in osmotic fragility, shortened erythrocyte survival time, increased serum lactic

dehydrogenase activity, increased fecal urobilinogen, and

mild reticulocytosis (1). These findings are the result of

a hemolytic component in aplastic anemia due to chronic

benzene exposure. Additionally, in some cases of

benzene-mediated aplastic anemia, absolute and relative

lymphocytosis are absent (1). In other words, in addition

to aplastic anemia resulting from other causes, absolute

lymphopenia is present in this hematologic disorder due

to chronic benzene exposure.
M. AKSOY

On the other hand, although there are no symptoms and

findings relating to the nervous system in aplastic anemia, idiopathic or because of different agents, in some

cases of aplastic anemia resulting from chronic exposure

to benzene, there are some findings relating to the nervous system (3). Although as early as 1967 Truhaut has

indicated in his reports on benzene the possibility of longterm effects of this chemical agent on the nervous system

such as polyneuritis of the lower extremities, there are

very few reports on this subject (3,4). Baslo and Aksoy

performed neurological, electromyographical, and motor

conduction velocity examinations in six patients with

aplastic anemia and two patients with preleukemia

caused by chronic exposure to benzene (3). In addition,

sensory conduction velocities were measured in three patients. Neurological abnormalities such as global atrophy

and decreased sensory vibration of lower extremities (in

one case), distal latency lengthening of median nerve (in

one case), decrease in the sensory conduction velocities

of the lower extremities (in one case) were found (3).

There was a certain relationship between the presence

of neurological abnormalities and the period of the exposure.

The findings of bone marrow examination in chronic

benzene toxicity are extremely variable. The picture

i-anges from complete aplasia to highly hyperplastic bone

marrow. In some patients, the bone marrow is fully acellular in the terminal stage (1). According to Mallory et al.

the effects of benzene on the bone marrow will vary with

the individual and are independent of the length of exposure (5). More than one type of foci can be encountered

in the bone marrow. Using 3H-methylthymidine autoradiography, Moeschlin and Speck studied the bone marrow

of animals poisoned by benzene and found that the results

varied from animal to animal: 4 very hypoplastic, 6

hypoplastic, 5 normocellular, and 4 hypercellular (6). No

correlation was found between cellularity of the bone

marrow and duration of exposure to benzene.

A follow-up study was performed in 44 pancytopenic patients with chronic benzene toxicity (7). Only 21 patients

had hypocellular bone marrow. It was normocellular in

13 patients and hypercellular in 8. Contrary to the flndings of peripheral blood, there was a relationship between

the types of cellularity of the bone marrow and the outcome, including the development of leukemia. Out of 21

patients with hypocellular bone marrow, 11 died (52.4%),

and in 5 patients (23.8%) leukemia developed later. Contrary to this, only 1 out of 13 (7.7%) pancytopenic patients

with normocellular bone marrow died. On the other hand,

4 out of 8 patients with hypercellular bone marrow recovered completely (50%). Two died from the complications

of aplastic anemia. In 1 of the remaining 2, leukemia developed and in the second 8 years after complete recovery, the occurrence of myeloid metaplasia was the cause

of death.

Ultrastructural studies in 4 patients with aplastic anemia and leukocytopenia were performed by Erbengi and

Aksoy (8). Electronmicroscopic findings were in accordance with the changes in the bone marrow observed by

light microscopy. Additionally, there was an increase in

plasma cells with maturation arrest in the later phases

of the erythroid series. Ultrastructural studies shed some

light on phagocytic activity of the reticulum cells. This

study showed a hyperactivation in the bone marrow of

one case and a depression in the erythroid elements in the

second patient. These different findings may give the impression that the effect of benzene on the bone marrow

may change from patient to patient.

Benzene-Hepatitis-Aplastic Anemia

Syndrome

The occurrence of aplastic anemia in chronic benzene

toxicity may be accelerated by the occurrence of viral

hepatitis. Recently we have observed a severe case of

aplastic anemia associated with chronic benzene toxicity

10 months after the appearance of hepatitis B. The

propositus was a 32-year-old technician working in a

petroleum plant (1). A sample of the product disclosed

2.2% benzene. Two years ago he had hepatitis B for a duration of 1 month. At that time he was not anemic and

there was no leukocytopenia or hemorrhagic diathesis.

Approximately 10 months later the signs of aplastic anemia appeared. He had severe pancytopenia. The bone

marrow was very hypocellular, and the findings were

consistent with the diagnosis of severe aplastic anemia.

The tests for hepatitis B-virus antigens determined by

ELISA showed that anti-HBs, anti-HBe, and anti-HBc

were positive. The clinical and hematologic picture of the

patient was similar to those of chloramphenicol-hepatitisaplastic anemia syndrome first described by Hodgkinson

(9). Following the failure of oxymetholon therapy, a trial

with anti-lymphocytic serum, the patient's clinical and

hematological picture improved considerably. He is in

remission at the present. We call this syndrome

"benzene-hepatitis-aplastic anemia syndrome"(1).

Benzene and Malignancies

Benzene is a suspected leukemogenic and carcinogenic

agent since the first description of a case of leukemia by

Le Noire and Claude in 1897 (10). Recently, Maltoni and

Scarnato showed in rats and mice that oral intake of high

doses of benzene causes malignancies in several tissues

(11). Any agent toxic to pluropotent stem cells can cause

an alteration in two important capabilities of the colony

forming cells (12): self-renewal and differentiation to produce a variety of lineage restricted progenitor cells, in

other words, the long-term maintenance of self-renewal

and differentiation. Any block or disturbance in these capabilities will cause either aplastic anemia (a block in selfrenewal) or leukemia (a block in differentiation). Therefore, benzene as a toxic agent for stem cells, may cause

aplastic anemia or leukemia.

Although there were numerous case reports showing

the possible role of benzene in the development of leukemia, the first epidemiologic study on this problem appeared in 1974 (13). From 1967 to September 1973, 26 patients with leukemia or pre-leukemia were seen among

194
HEMATOTOXICITY AND CARCINOGENICITY OF BENZENE

Table 1. Annual number of leukemic shoe workers in Istanbul

between 1967 and 1978.

Year No. of leukemic shoe workers

1967 1

1968 1

1969 3

1970 4

1971 6

1972 5

1973 7

1974 4

1975 3

1976 0

1977 0

1978 0

28,500 shoe-slipper and handbag workers chronically exposed to benzene in Istanbul. At that time, the concentration of benzene was found to reach a maximum of 210

to 650 ppm during working hours in workplaces. The content of benzene in adhesives and thinners was between

9% and 88% (7,14). Of these leukemic workers, 17 were

investigated at the Second Internal Clinic of Istanbul

Medical School. The remaining 9 leukemic workers were

studied in other hospitals in Istanbul. As explained in this

study, another worker with acute lymphoblastic leukemia

resulting from benzene exposure was not included in this

series because his profession was different. In 1974, the

number of the leukemic shoe workers in Istanbul increased to 31 (15). Thus the incidence of leukemia among

them was 13.59 per 100,000, which is a markedly and

statistically significant increase over that of leukemia in

general population, 6 per 100,000.

In Turkey, according to the official Year Book of Health

Statistics, the incidence of leukemia is between 2.25 and

2.80 per 100,000 (16). As can be seen from Table 1, the

peak incidence among shoe workers in Istanbul occurred

between 1971 and 1973 (17). It was 21.7 per 100,000. The

number of leukemic shoe workers in Istanbul started to

decrease after the prohibition and discontinuation of the

use of benzene since 1969 (17). The number of new leukemic shoe workers has decreased in 1974 to 1975 to the

level of 1969 to 1970, and none were recorded in subsequent 3 years. But between 1979 and 1987, we observed

22 new cases of leukemia associated with chronic exposure to benzene. Only 3 of them were shoe workers living in Istanbul. The decline in the annual occurrence of

leukemia in the series of shoe workers in Istanbul may

be attributed to the prohibition and gradual discontinuation of benzene in this city starting in 1969. On the other

hand, the reappearance of leukemia after 1979 in Istanbul and other Turkish cities may be attributed either to

the variation in the interval between the occurrence of

leukemia and exposure or the continued use of materials

containing benzene (17).

The evidence for the use of benzene in Istanbul and

other cities of Turkey following the prohibition of this

chemical is shown in the following study (18). To illustrate

the etiologic role of drugs and chemicals in the development of aplastic anemia, we analyzed 108 cases of aplastic anemia among 3175 hematologic patients during a

10-year period (1973-1982) in the hematology section of

the Istanbul Medical School (18). In 25 (23.1%) of the

cases, benzene was responsible for the development of

aplastic anemia. On the other hand, a recent study performed in the period between 1983 and 1985 in Istanbul

and Izmit showed that despite the considerable decrease

in the content of benzene in most of the materials, they

were still above permissible limits (19). During the study

mentioned above we have encountered 2 cases of acute

leukemia in a modern tire cord fabric in Izmit (19). Approximately 550 workers were employed. The working

conditions were good and properly ventilated. The concentration of benzene in one part of the plant was 110

ppm, and in one solvent used in the auxillary repair shop

the benzene content was nearly 5%. The incidence of

leukemia was 60.6 per 100,000 in a period of 6 years.

Development of Leukemia in Pancytopenic

Patients with Chronic Benzene Toxicity

In our series comprising 59 leukemic patients with benzene exposure, a preceding pancytopenic period was present in 14 leukemic patients (23.7%) (20). The interval between the onset of the preceding pancytopenic period and

that of leukemia varied between 6 months and 6 years.

Furthermore, in a follow-up study in 44 pancytopenic patients with chronic benzene toxicity, leukemia developed

in 6 (13.6%) and myeloid metaplasia in 1 (2.8%) (7).

Familial Connection and Individual

Susceptibility

As can be seen from Table 2, in 6 leukemic patients associated with chronic benzene exposure, in our series, a

Table 2. Genetic relationship between eight leukemic patients with chronic exposure to benzene or colchicine and saccharin.

Case no. Age Duration of exposure, years Occupation Type of leukemia Genetic relationship

1 43 6 Shoe worker AML Paternal uncle of case 2

2 24 4 Shoe worker AML Nephew of case 1

3 36 7 Shoe worker AML Maternal cousin of case 4

4 48 3 Painter AML Maternal cousin of case 3

5 36 15 Shoe worker Erythroblastic leukemia Son of case 6

6a 65 35 Shoe worker Unidentified type of leukemia Father of case 5

7 43 2 Owner of a Chronic lymphoid leukemia Son of case 8

wallpaper and

printing shop

8b 77 10-20 tablets daily Stationer Chronic lymphoid leukemia Father of case 7

"This case was not included in our series of leukemia because he was not studied before his death.

bUsed colchicine and saccharin.

195
M. AKSOY

familial connection was established (1,15,21).* Two were

an uncle and his nephew, and 2 were cousins (15). The

father of the fifth leukemic patient, a 65-year-old shoe

worker with a long history of benzene exposure, died in

a hospital with the diagnosis of myelosclerosis, but reevaluation of the case report showed that this patient had

acute leukemia of an unidentified type (15). The father of

the seventh patient with chronic benzene exposure also

had the same hematologic malignancy associated with the

use of colchicine and/or saccharin (21). These 6 leukemic

patients among the first- and second-degree relatives constituted 10.2% of the leukemic patients with chronic exposure to benzene.* In these 6 patients including case 7,

the development of leukemia possibly resulted from

simultaneous presence of genetic determinants, in addition to benzene as an extraneous or environmental factor. This suggestion is in accordance with the view that

leukemia may be caused by the combination of various intrinsic and extrinsic factors (22). On the other hand, family susceptibility in the development of various disorders

of chronic benzene toxicity suggested by numerous investigators were evident in our studies concerning benzene

toxicity (1,1 7).

Types of Leukemia in Chronic Benzene

Toxicity

It is evident from the literature that there is a significant difference in the distribution of leukemia types

caused by benzene exposure (1,15,20,23). In one group,

acute types of leukemia, mostly myeloblastic or erythroblastic, predominate, and in the other chronic leukemia,

myeloid and lymphoid take the most important place. Although in our series, acute leukemia was 89.8%, the percentage of chronic types comprising myeloid, lymphoid,

and hairy cell leukemia was 10.2% (20). Considering these

facts we have tried to explain the possible factors that

may determine the types of leukemia in chronic benzene

toxicity (23).

One factor may be the differences in the content of benzene in the material used. The benzene content of the

adhesives and thinners used by workers with acute leukemia in our series was very high (13,15,17,23). In contrast,

it was very low (2.8%) in a worker with chronic lymphoid

leukemia (23). Second, the adhesives and thinners that

were used by nearly all the workers with acute leukemia

contained only benzene (13,15,23). Contrary to this, the

solvent used by a worker with chronic lymphoid leukemia had a low level of benzene and a high percentage of

toluene (23). Third, the great majority of the individuals

with acute leukemia in the series was exposed to high

concentration of benzene ranging between 150 and 210

ppm during all working hours (13,15,23). Contrary to this,

5 out of 6 patients with chronic leukemia, 2 with chronic

myeloid, 2 with chronic lymphoid, and one with hairy cell

*Cases 6 and 8 were not included in this series because one (case 6)

was studied in another hospital and the second (case 8) was not exposed

to benzene (15,21).

leukemia were exposed to benzene intermittently and for

a short time during the daily work. Fourth, the possible

role of genetic factors may help to explain the development of different types of leukemia. As can be seen from

Table 2, 6 patients in 3 families had acute types of leukemia. In the fourth family, despite different extraneous

factors such as chronic benzene exposure and the use of

colchicine and/or saccharin, the same type of leukemia,

namely chronic lymphoid, developed at different ages

(21).

Benzene, Malignant Lymphoma, Multiple

Myeloma, and Lung Cancer

There are a few investigations that suggest a possible

role of benzene in the etiology of malignant lymphoma,

multiple myeloma, and lung cancer. In 1961, Wirtschafter

and Bichell showed that tissue responses could be observed in lymph nodes, spleen, thymus, and bone marrow

of the rat after a single injection of benzene (24). Recently, Irons et al. showed that the effects of benzene administration in mice on lymphocyte function are at the

doses of the compound that produce little or no measurable differences in the number of circulating cells (25). In

1974, we described 6 cases of Hodgkin's disease with

chronic exposure to benzene (26). Despite the lack of

statistical data, we suggested that chronic exposure to

benzene might play a role in the development of Hodgkin's disease.

In the last few years we have studied 7 more cases of

different types of malignant lymphoma with benzene exposure (1,17,19). In 1979, Vianna and Polan performed a

comparative study on the mortality rates of different

types of malignant lymphoma among workers exposed to

benzene (2?). According to the investigators, their results

are consistent with the possibility that chronic exposure

to benzene might be important in the etiology of malignant lymphoma. A recent study of Norseth et al. is also

in favor of this assumption (28). Furthermore, there are

several studies showing a high mortality rate from different types of malignant lymphoma among pathologists,

chemists, and persons handling chemicals containing benzene (29).

Multiple Myeloma

As early as 1970, Torres et al. reported 2 cases of multiple myeloma with chronic benzene exposure (30). In

1980 and 1984, we described 4 cases of multiple myeloma

with chronic benzene exposure (31,32). Only one of these

patients had a short period of pancytopenia with

hypoplastic bone marrow. The mean exposure time to

benzene was longer than that of cases of leukemia and

malignant lymphoma: 18 years in the former and 10.5 in

the latter (1). In an epidemiologic assessment study of

Rinsky et al. in 1987, there was a statistically significant

increase in deaths from leukemia and multiple myeloma

(33).

196
HEMATOTOXICITY AND CARCINOGENICITY OF BENZENE 197

Lung Cancer

In 1976, we considered 5 individuals with lung cancer

associated with chronic benzene exposure and suggested

that there is a causal relationship between this chemical

and lung cancer (34). In our series of malignancies resulting from chronic exposure to benzene, there are 7 cases

of lung cancer (1,17). Only 3 showed mild hematologic

findings of chronic benzene toxicity. Because benzene

available in Turkey did not contain benzo[alpyrene determined by ultraviolet spectrophotometry, lung cancer in

these 7 patients cannot be attributed to this carcinogenic

agent (1,7). Benzene is mainly absorbed via the lungs, and

about 40% of the absorbed portion is exhaled unchanged

(35). After 24 hr, a small percentage of benzene can still

be detected in the expired air (35). Therefore, a carcinogenic effect of benzene in the lung is possible. Because

our patients were also smokers, a contributory role of

smoking in the development of lung cancer is possible.

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