literary review

Article

Benzene-contaminated toluene and acute myeloid leukemia: a case series and review of literature

Trevor Peckham1, Melvyn Kopstein2, Jason Klein1

and James Dahlgren 1

Abstract We report seven cases of acute myeloid leukemia (AML) with occupational exposure to a toluene-based hydrocarbon solvent. The cases were employed at a facility, which manufactured rubber belts and hoses, between 1950 and 2005 for periods ranging from 21 to 37 total years. Detailed histories were obtained for three workers who were diagnosed with AML within a 3-year period (2003–2005). Death certificates, medical records, and accounts by workers were reviewed. Benzene, a known cause of AML, is typically a contaminant of toluene. Benzene contamination in toluene and other widely used solvents and the potential for concurrent benzene exposure during usage of these solvents in occupational settings are discussed.

Keywords Benzene, acute myeloid leukemia (AML), toluene, occupational exposure, hydrocarbon solvent

Introduction

Benzene, a well known cause of myelodysplastic

syndrome (MDS) and acute myeloid leukemia (AML)

(Baan et al., 2009; IARC, 1987; Smith, 2010), is pres-

ent as a contaminant in many common petrochem-

icals, including toluene, mineral spirits, and naphtha

(Kopstein, 2011). Recent studies indicate that use of

hydrocarbon solvents with benzene content of

<0.1% can create breathing zone benzene air concen- trations that surpass occupational limits (Fedoruk

et al., 2003; Kopstein, 2006) (Table 1). Similarly,

occupational exposure via dermal absorption to mix-

tures containing <0.1% benzene may significantly increase cancer risk (Brenner et al., 1998; Kalnas and

Teitelbaum, 2000; Petty et al., 2011).

We present seven cases of AML in workers with

occupational exposure to a toluene-based hydrocar-

bon solvent in a factory that manufactured rubber

belts and hoses. Case-specific information on a subset

of former employees was retrieved from death certif-

icates, medical records, and accounts from workers.

The AML cases were employed at the rubber plant

between 1950 and 2005 for periods ranging from 21

to 37 total years. Detailed occupational and medical

histories were obtained for three of the cases who

developed the disease between 2003 and 2005. The

toluene-based solvent was used for cleaning and

removing misprints on manufactured rubber items

and for cleaning ink from printing presses and is the

only solvent identified by former workers. No infor-

mation regarding other solvents being used at the

facility or data regarding the benzene content of the

toluene solvent were available for this assessment.

Employees specify that personal protective equip-

ment (i.e. respirators, impervious clothing, or gloves)

were rarely, if ever, utilized when working with the

toluene solvent. The solvent was applied to a rag or

brush and used without gloves, creating both inhala-

tion and dermal exposures. There was no local

exhaust ventilation or other engineering controls pres-

ent in the workspace.

1James Dahlgren Medical, Santa Monica, CA, USA 2Potomac, MD, USA

Corresponding author: James Dahlgren, James Dahlgren Medical, 1158 26th Street, 118, Santa Monica, CA 90403, USA. Email: [email protected]

Toxicology and Industrial Health 2014, Vol. 30(1) 73–81 © The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0748233712451764 tih.sagepub.com

Case presentation

Case 1, a white male, worked at the facility from 1968

until 1994. In early 2003, he was diagnosed with pan-

cytopenia. In December 2003 at the age of 72 years, a

bone marrow biopsy showed AML with multilineage

dysplasia. He had preexisting MDS. Cytogenetic

analysis at this time revealed the presence of an

abnormal hypodiploid clone characterized by loss of

chromosomes X, 3, 5, 6, and 18, additional material

of unknown origin on 4q, 10p, 12q, 13p, and 21p,

an inverted duplication of 7p, a derivative chromo-

some resulting from deletions of both the long and

short arms of chromosome 16, and a marker chromo-

some. In February 2004, a second cytogenetic analy-

sis revealed the clonal expansion of an abnormal

hypodiploid cell. The abnormal clone was the loss

of chromosome 5, additional material of unknown ori-

gin on the short arm of chromosome 6, and the long

arm of X chromosome. Nine cells were normal male.

These findings are consistent with a clinical diagnosis

of MDS or AML. He completed six cycles chemother-

apy with idarubicin and ara-C. In July 2004, he

relapsed and died from leukemia and congestive heart

failure. He smoked cigarettes until 1988, but total

pack-years could not be determined. His work history

was provided by a coworker with a similar job. Case 1

transferred the toluene solvent into one-half gallon

containers with spring-loaded tops and provided fresh

solvent to six work stations as often as once per shift.

He spent about 50% of his day sorting and cleaning the belts, which involved using the toluene solvent

on a rag to wipe incorrectly printed or dirty belts.

He used no personal protective equipment.

Case 2, a white female, worked at the facility from

1965 until 1995. She presented with thrombocytope-

nia, anemia, and leukocytosis and was diagnosed with

AML in November 2005 at the age of 58 years. Mole-

cular cytogenetic studies were negative for abnormal

fusion of clones of the PML gene on 15q to the RARA

gene on 17q. Specifically, there was no evidence of

the t(15;17)(q22;q11.2) translocation in this speci-

men. Additional studies were also negative for the

rearrangement of the mixed lineage leukemia region

at 11 q23. The bone marrow and peripheral blood

showed >20% blasts. The percentage of myeloid lines that had >50% dysplasia was not specified, and clas- sification using World Health Organization criteria

was not possible. Case 2 was classified as AML-M4

under the French–American–British (FAB) Coopera-

tive Group criteria due to having dysplastic mono-

cytes. Chemotherapy with idarubicin and ara-C and

eventually cytarabine was given inducing a remission.

She relapsed May 2006 and died. She was a nonsmo-

ker. She described her work activities at the plant

shortly before her death. Similar to Case 1, she also

worked in the prepack department. Her main task was

printing and packing the rubber belts. She obtained

containers of the toluene solvent from Case 1, who

was the service man assigned to her workstation. She

would dip brushes or rags into the solvent containers

to clean the belts. When the belt printer malfunc-

tioned, it had to be cleaned using large amounts of the

solvent, a high exposure task. She rarely wore gloves,

and the solvent made her fingertips raw, causing open

sores on her hands.

Case 3, a white male, worked at the facility

between 1984 and 2005. He was noted to have leuko-

cytosis and malaise in May 2003. He continued work-

ing with a diagnosis of myeloproliferative disorder

(MPD), subtype not otherwise specified. Some of his

hematologists opined that he had MDS based on white

blood cell count, which was >12,000, and <5% of monocytosis and blasts in the bone marrow. His treat-

ment included hydroxyurea. His MPD/MDS trans-

formed to AML with multilineage dysplasia in June

2005, at the age of 53 years. The only cytogenetic

Table 1. Occupational exposure limits for benzene concentration in air.

Agency Description Level (ppm) Reference

OSHA Permissible exposure limit 8-hour TWA 1.0 OSHA, 1987 STEL 5.0

ACGIH Threshold limit value TWA 0.5 ACGIH, 2006 STEL 2.5

NIOSH Recommended exposure limit (10-hour TWA) 0.1 NIOSH, 1986, 2005 STEL 1.0

OSHA: Occupational Safety and Health Administration; ACGIH: American Conference of Governmental Industrial Hygienists; NIOSH: National Institute for Occupational Safety and Health; TWA: time weighted average; STEL: short time exposure limit; ppm: parts per million.

74 Toxicology and Industrial Health 30(1)

studies performed on this patient showed a normal

male karyotype. Fluorescence in situ hybridization

cytogenetic studies, as well as a PCR study, were neg-

ative for 9;22 translocation. No abnormal clones were

detected at this band level. The patient started induc-

tion chemotherapy with idarubicin and received a

bone marrow transplant in December 2005. He died

in July 2006 from his leukemia while in hospice care.

This man had a 5-pack/year smoking history, which

ended before 1985. Case 3 worked many years in

departments that built the rubber belts. Coworkers

reported that this process involved using the toluene

solvent in a similar manner as Cases 1 and 2, that

is, cleaning misprinted or dirty belts. A fellow

employee described the use of this solvent two or

three times a day from small squirt bottle. Case 3 was

responsible for filling his bottle from a container by

pumping by hand.

Four other employees from this facility with prob-

able exposure to the toluene-based solvent presented

with AML diagnosis. Death certificates of these addi-

tional cases were reviewed, but other information is

limited (Table 2). These cases were revealed during

the course of discovery for civil litigation involving

the three index cases. Two of the four have confirmed

history of building or packaging belts, similar to index

cases. These additional cases are presented due to the

similar time frame of employment. No follow-up has

been performed to our knowledge, and there may be

other former employees with parallel diagnosis and

exposure histories. All but one AML case were

employed at the facility beginning in the 1950s or

1960s. Evidence was also obtained for 14 additional

workers from this plant with other lymphohemato-

poietic cancers. Medical records, death certificates,

and other information were collected from family and

coworkers for the group of all 14 workers, which

included reports of diagnoses of chronic lymphocytic

leukemia (4 workers), non-Hodgkin’s lymphoma

(8 workers), and multiple myeloma (2 workers). Only

cases of AML confirmed by death records are

reported herein.

Discussion

Data collected on a subset of past employees from this

rubber belt plant indicate seven AML deaths between

1994 and 2006. Lancaster County, Nebraska eco-

nomic census data indicate that the plastics and rubber

manufacturing industries (North American Industry

Classification System code 326) employed between

1000 and 2499 workers in 2002 (US Census Bureau,

2002). This range also includes 500 and 999 employ-

ees from plastics manufacturing facilities, while the

presented cases worked at the only facility in the

county classified as rubber products manufacturing.

At least seven deaths in a 12-year span at a facility

of less than 2000 workers likely represent an elevation

in AML mortality. The county population in 2000 was

250,291 (US Census Bureau, 2000). The US national

age-adjusted mortality from AML in men and women

of all races above the age of 50 years in 2005 is 8.57

per 100,000 population (NCI, 2011). It is notable that

four cases expired between 2002 and 2006, two of

which had worked in the same department. The

Nebraska Cancer Registry reports 89 total leukemia

deaths in the county during this period, and that AML

accounted for approximately 27% of all leukemia cases in the state from 2003 to 2007 (Nebraska Cancer

Registry, 2010). Using this percentage, the presented

AML deaths from this facility would hypothetically

represent 17% (4 of 24) of all AML mortality in the county between 2002 and 2006.

Cigarette smoking may have contributed to an

increased risk of AML from benzene exposure within

tobacco smoke in Cases 1 and 3; however, each of

Table 2. AML in employees at rubber belt and hose plant.

Case no. Gender Diagnosis

Year of birth

Year of diagnosis

Year of death

Age at death

Years of employment

Employment length

1 M MDS and AML 1931 2003 2004 73 1968–1994 26 2 F AML 1947 2005 2006 59 1965–1995 30 3 M MPD and AML 1952 2005 2006 54 1984–2005 21 4 M MDS and AML 1927 – 1998 71 1950–1980 30 5 F MDS and AML 1937 – 2003 66 1960–1997 37 6 M AML 1930 1994 1994 63 1954–1989 35 7 F AML 1922 – 2001 79 – –

AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; MPD: myeloproliferative disorder; M: male; F: female.

Peckham et al. 75

these cases stopped smoking over 15 years before

their AML diagnoses. The cancer risk associated with

cigarettes has been reported to diminish over time

(Richardson et al., 2008). Smoking data was not

available for the four auxiliary cases. Newly diag-

nosed AML patients have a median age of 65 years

(Deschler and Lubbert, 2006). Cases 2 and 3 were

under the age of 60 years at time of death, while the

average age of the seven AML deaths was 66.4 years.

There is no indication of other leukemia risk factors in

this group, such as exposure to radiation, formalde-

hyde, or prior chemotherapy. We propose that

decades of occupational exposure to benzene present

in the toluene-based solvent used at the facility likely

caused or contributed to the development of AML.

Inference of benzene contamination in the toluene

solvent is supported by the physicochemical proper-

ties of toluene, reports of usage of toluene and other

hydrocarbons leading to benzene air concentrations

above occupational limits, reports of benzene-

related disease from toluene exposure, and toluene

material safety data sheet (MSDS) reporting up to

5% benzene as recent as 2008 (Table 3). The International Agency for Research on Cancer

(IARC) classifies toluene as a group 3 carcinogen,

indicating that the data are insufficient to implicate

carcinogenicity to humans (IARC, 1989). Usage of

organic solvents such as toluene in occupational

settings often lead to overlapping exposures, as they

contain multiple aromatic and aliphatic hydrocarbons

as impurities. Reports from the 1940s describe

toluene-exposed workers exhibiting typical benzene-

related hematological effects (Greenburg et al.,

1942; Wilson, 1943), which are now attributed to the

presence of benzene as a contaminant (ATSDR,

2000). A recent study specifically investigated over-

lapping exposures to organic solvents and concluded

that benzene present in aromatic solvent mixtures was

likely to be responsible for the observed elevations in

leukemia and lymphoma (Cocco et al., 2010).

As early as 1977, a significant increase in total

lymphohematopoietic and leukemia deaths was seen

in a group of rubber workers exposed only to benzene

(Infante et al., 1977; Rinsky et al., 1981). Subsequent

research has confirmed the ability of benzene to cause

malignant and nonmalignant hematopoietic disorders

and suggests that increased risk occurs at levels mark-

edly lower than first reported (Hayes et al., 1997,

2001). In particular, Glass et al. (2003) found, in a

case–control study of the Health Watch cohort, that

the risk of leukemia was increased at all cumulative

exposures above 2 parts per million (ppm)/years with

no evidence of a threshold cumulative exposure

below which there was no risk (Glass et al., 2003).

Prior to reliable epidemiological data, benzene had

already been deemed as a leukemogen and potent

hematotoxin due to an ample collection of case report

series (Aksoy et al., 1974; Vigliani and Forni, 1976).

We have included available chromosomal studies

in the three index AML cases. There is currently an

interest in collecting this data to guide therapy and

estimate prognostic differences. A chromosomal pat-

tern or fingerprint that is unique for benzene has been

suggested (Gillis et al., 2007); however, available data

do not support this claim (Smith, 2008).

Benzene as a contaminant of toluene and other petrochemicals

American Society for Testing and Materials Interna-

tional (ASTM) has published specifications for the

properties of nitration and industrial grades of toluene

(ASTM, 1984, 2002). The maximum boiling range

establishes the specified purity of both the grades of

toluene, and the temperature at which a toluene/benzene

mixture starts to boil corresponds to the equilibrium

molar concentration of benzene at that temperature.

Toluene’s boiling point is 110.6�C. For the nitration grade toluene, the boiling range must be �1�C, and for the industrial grade toluene, the boiling range is

Table 3. Benzene content of toluene in MSDS issued after 2000.

Product Benzene content (ppm) by weight

Benzene content (% by weight) Reference

Commercial grade toluene 20,000 (up to 50,000) 2–5% Equistar Chemicals LLP, 2008a Nitration grade toluene 20,000 (up to 50,000) 2–5% Equistar Chemicals LLP, 2008b Nitration toluene Up to 10,000 Up to 1% ExxonMobil Chemical, 2002 Nitration toluene Up to 10,000 Up to 1% ExxonMobil Chemical, 2003 Commercial grade toluene Up to 25,000 Up to 2.5% Chevron Phillips Chemical Company, 2003

MSDS: material safety data sheet; ppm: parts per million.

76 Toxicology and Industrial Health 30(1)

expanded to 2�C. Using a recirculation type vapor– liquid equilibrium apparatus at a temperature of

107.04�C, benzene comprised 8.1%, or 81,000 ppm, of the benzene/toluene mixture (Kesselman et al.,

1968). Similar analysis reveal that toluene solvent meet-

ing ASTM’s boiling point range specification for nitra-

tion and industrial grades may have between 22,900 and

44,800 ppm benzene on a volume basis, or approxi-

mately 2–4.5% (ASTM, 1984, 2002; Kopstein, 2011). Toluene not meeting ASTM specifications may have

a wider boiling point range and much more benzene.

Analytical difficulties in measuring lower levels of ben-

zene in mixtures has been noted by Sheehan et al.

(2010), Kopstein (2006, 2008), and OSHA (1980).

MSDS issued after 2000 shows benzene content of

toluene as high as 5% and comport well with the phys- ical chemistry properties (Table 3).

Published scientific literature (Aksoy et al., 1987;

Angerer, 1979; Baenfer, 1961; Browning, 1965;

Kasahara et al., 1987; Mehlman, 2004; Novaes and

Gruenzner, 1981) and other peer reviewed sources

(ACGIH, 1991; EPA, 1994; NIOSH, 1973; WHO,

1985) discuss benzene contamination in petrochem-

ical products, which is as high as 25% in toluene. Occupational health textbooks have warned that

toluene may contain significant amounts of benzene

(Levy, 1995; McCunney, 1994), and it has been rec-

ommended that workers exposed to toluene undergo

hematological examinations due to benzene contami-

nation (Sittig, 1985; Zenz, 1975). Conversely, publi-

cations emanating from members of the American

Chemistry Council Hydrocarbon Solvents Panel—

which is comprised entirely of CITGO Petroleum,

ExxonMobil Chemical Company, Flint Hill

Resources LP, Sasol N.A., and Shell Chemicals

LP—have argued that benzene concentration in

hydrocarbon solvents has been minimal subsequent

to an unspecified date in the late 1970s, citing unpub-

lished data (Caldwell et al., 2000; Jaques, 2006;

McKee et al., 2007).

Toluene and exposure to benzene

Several reports document use of toluene products in

occupational settings contributing to significant air

benzene concentrations—even if benzene is absent

from labeling or MSDS. In a German case report, a

woman using an adhesive with a reported 27% toluene content developed aplastic anemia. Subse-

quent air measurements found the presence of 11 ppm

toluene and 8 ppm benzene, although the latter was

not included in the product’s label (Lachnit and

Reimer, 1959). Analysis of a paint factory in Iran

focused on the efficacy of exhaust ventilation systems

to reduce the workers’ exposure to toluene and

xylene. The authors reported benzene air concentra-

tions averaging 31.98 ppm in the breathing zones of

workers. Benzene was not reported as a component

of the paint. The benzene air concentration was

lowered to 4.5 ppm after the HVAC systems were

activated, still many times higher than the US occupa-

tional exposure limit. These authors concluded that

benzene air level monitoring was needed for solvents

likely or possibly contaminated with benzene, even if

benzene is not listed on the MSDS (Jafari et al., 2009).

A case series similar to the present report portrayed

two workers diagnosed with chronic myelogenous

leukemia and thrombocytopenia after exposure to

toluene during employment in the printing trade. In

addition to toluene, the workers reported using methyl

ether ketone (MEK), which is not known to be carci-

nogenic. Exposures of workers were profiled using

information provided in interviews and a review of lit-

erature and relevant reports. The author attributes the

development of these diseases to benzene exposure

arising from the contaminated toluene, and stressed

the importance of the retrospective exposure profiles

based on worker interviews and workplace descrip-

tions in the absence of air monitoring data or access

to the workplace (Kudla, 1997).

Hydrocarbon solvents and dermal exposure to benzene

American Conference of Governmental Industrial

Hygienists (ACGIH) has issued a ‘skin notation’ to its

recommendations on benzene exposure, indicating that

dermal absorption of benzene can contribute signifi-

cantly to the body burden in humans and air sampling

alone is insufficient to accurately quantitate exposure

(ACGIH, 2006). Repeated exposure to toluene solvents

induces irritation and may injure the skin with cracks,

lesions, and open sores and allow benzene to cross the

skin barrier and enter the bloodstream (ATSDR,

2007; Blank and McAuliffe, 1985). Occupational

Safety and Health Administration (OSHA) noted that

‘appreciable quantities of benzene could be absorbed

in the case of injured skin. Moreover, absorption of

benzene by the skin may be significantly accelerated

when benzene is present as a mixture or as a contami-

nant in solvents known to be readily absorbed such as

toluene and xylene’ (OSHA, 1977).

Peckham et al. 77

Brenner et al. report the case of a man who devel-

oped aplastic anemia after using mixture of acetone,

MEK, and toluene during the cleaning and coating

of pipes over a 30-year-period. The authors estimated

that benzene was present in varying concentrations

(0.3-4.5% from 1963 to 1978, 0.03-0.3% from 1978 to 1983, and 0.003-0.03% from 1983 to 1993). The mixture was consistently splashed on the workers

hands and forearms and occasionally other body parts.

Dermal dose of benzene was estimated as equivalent

to an inhalation exposure of 170 ppm/year (Brenner

et al., 1998). Kalnas and Teitelbaum (2000) estimated

that a worker who exposes his hands and lower fore-

arms to cleaning solvent containing 0.1% benzene for 2 minutes every 15 minutes throughout the work day

will absorb through the skin an amount of benzene

equivalent to breathing air with 0.7 ppm benzene or

a cumulative exposure of 28 ppm/year in a hypotheti-

cal 40-year period. This report also mentions several

additional case reports of hematological effects after

dermal exposures to liquids containing 0.1% or less benzene (Kalnas and Teitelbaum, 2000). A recent

study using a more comprehensive approach obtained

similar estimates as Kalnas and Teitelbaum (Petty

et al., 2011).

Eight Finnish mechanics were at risk of benzene

exposure while performing fuel system repairs and

were subjected to air and blood sampling. The authors

attributed >65% of total benzene exposure to the der- mal route after blood benzene levels were higher than

could be expected according to the corresponding

time weighted averaged air measurements (Laitinen

et al., 1994). Similarly, 60% of total benzene dose was credited to dermal absorption in a series of experi-

ments monitoring showers in a home with benzene-

contaminated water (Lindstrom et al., 1994).

Hydrocarbon solvents and inhalation exposure to benzene

A database for occupational exposure to hydrocarbon

solvents was reported by Caldwell et al. (2000). The

authors tabulated data on more than 700 published

personal breathing zone exposures to benzene between

1978 and 1997, averaging 13.75 ppm (Caldwell et al.,

2000). The authors characterize their findings as a

‘reality check,’ and report that many workplaces did

not have proper engineering controls. This is highly

relevant since the OSHA Benzene Standard stipulates

that a combination of engineering controls and work

practices are needed to reduce the 8-hour time

weighted average work exposure to below 1 ppm

(OSHA, 1987).

Fedoruk et al. investigated the benzene content and

subsequent air concentrations associated with the

usage of a mineral spirits-based degreaser formulated

with severely hydrotreated mineral spirits. The assess-

ment was designed to simulate parts by washing with

severely hydrotreated mineral spirits in a degreaser

station using a wet brush and sprayers. The simulated

work environment did not have any engineering con-

trols. The experiment measured a benzene air concen-

tration of 0.55 ppm when testing a mixture containing

58 ppm benzene (0.0058%) (Fedoruk et al., 2003). Kopstein utilized Fedoruk’s experimental exposure

data, employing thermodynamics and mass transfer

principles to estimate exposures to benzene arising

from products containing higher concentrations of

benzene in the mineral spirit mixture (Table 4).

Kopstein’s results apply to working conditions similar

to the Fedoruk study (Kopstein, 2006). Both Fedoruk

et al. and Kopstein conclude that products containing

<0.1% benzene can potentially produce air benzene levels that exceed occupational exposure limits.

Regular mineral spirits contains far more benzene

than the severely hydrotreated mineral spirits used

in the Fedoruk study (Hunting et al., 1995; IPCS,

1996; Kopstein, 2011). Using a near field/far field

model, Nicas et al. (2006) reported benzene exposures

comparable with those measured by the Fedoruk

simulation.

Three studies sponsored by industry have found or

modeled benzene levels to be much lower than

measurements cited above. Sheehan et al. modeled

benzene inhalation and dermal exposures arising from

the use of solvents containing very-low concentra-

tions of benzene, finding breathing zone benzene con-

centrations below detection limits (Sheehan et al.,

Table 4. Airborne benzene from use of petroleum- derived products.

Mean benzene content of petroleum-derived solvent (ppm, v/v)

Percentage benzene

by volume

1 hour TWA benzene

concentration (ppm)

55.2 0.005% 0.5 110.4 0.011% 1.0 552 0.055% 5.0 1000 0.1% 9.1 5000 0.5% 45.3

Adapted from Taylor and Francis (Kopstein, 2006). TWA: time weighted average; ppm: parts per million.

78 Toxicology and Industrial Health 30(1)

2010). Another modeling study estimated air benzene

values using values from non peer reviewed literature

for model inputs and predicted air levels would rarely

exceed ACGIH or OSHA air levels (Williams et al.,

2008). The third modeling study minimized exposures

by creating a novel pattern of usage (e.g. complete

evaporation or paper-thin solvent layers) assuring

low-measured values (Paustenbach et al., 2010).

Conclusions

Case reports have been vital to the understanding of

benzene toxicity, as well as other chemicals, and

remain so today. Based on available information, the

similar, long-term exposure to a toluene-based sol-

vent experienced by the three primary AML cases and

toluene’s propensity to contain benzene as an impur-

ity suggest benzene as a probable causative factor for

their development of this disease. Although the ben-

zene concentration in widely used solvent mixtures

varies, there is a reason to believe that even those con-

taining amounts <0.1% have the potential to generate exposures capable of causing AML among industrial

workers. Past research has focused on inhalation as

the primary route of benzene exposure; however, der-

mal absorption is a critical route of exposure for cer-

tain occupations.

Acknowledgements

We thank Maria Dominguez and Savanna Carson for their

comments and help in revising the manuscript.

Conflict of interest

JD and MK are sometimes retained as experts in civil cases

regarding exposure to benzene.

Funding

Original funding for the assessment of the three index cases

was provided by a law firm representing plaintiffs in a civil

lawsuit. The writing of the manuscript was entirely funded

by the JD.

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