SUBSTANCE PROFILES

REPORT ON CARCINOGENS, ELEVENTH EDITION

Isoprene

CAS No. 78-79-5

Reasonably anticipated to be a human carcinogen

First Listed in the Ninth Report on Carcinogens (2000)

Carcinogenicity

Isoprene is reasonably anticipated to be a human carcinogen based on

sufficient evidence of tumor formation at multiple organ sites in

multiple species of experimental animals (Melnick et al. 1994, NTP

1995, 1997, Placke et al. 1996). Inhalation exposure of mice to

isoprene vapors induced increased incidences of neoplasms of the

lung, liver, harderian gland, forestomach, hematopoietic system, and

circulatory system. Inhalation exposure of rats to isoprene vapors

induced increased incidences of neoplasms of the mammary gland,

kidney, and testis (IARC 1999). 

No adequate human studies of the relationship between exposure

to isoprene and human cancer have been reported. 

Additional Information Relevant to Carcinogenicity

Isoprene is the 2-methyl analog of 1,3-butadiene, an industrial chemical

that has been identified as an animal and human carcinogen. Isoprene

and butadiene are metabolized to monoepoxide and diepoxide

intermediates by liver microsomal cytochrome P450-dependent

monooxygenases from several species, including humans. Detoxification

of these intermediates may occur by hydrolysis catalyzed by epoxide

hydrolase or conjugation with glutathione catalyzed by glutathione-Stransferase. The diepoxide intermediates of isoprene and butadiene are

mutagenic in Salmonella typhimurium, whereas the parent compounds

are inactive (Gervasi et al. 1985). In mice, isoprene and 1,3-butadiene

induced sister chromatid exchanges in bone marrow cells and increased

the frequency of micronucleated erythrocytes in peripheral blood (Tice

et al. 1987, Tice et al. 1988). Common sites of neoplasm induction by

isoprene and butadiene include the mammary gland and testis in rats,

and the liver, lung, harderian gland, forestomach, and circulatory system

in mice (NTP 1997). Lung and harderian gland neoplasms induced by

isoprene in mice had a high frequency of unique K-ras mutations (A to

T transversions at codon 61) (Hong et al. 1997).

No data were available that would suggest that mechanisms

thought to account for tumor induction by isoprene in experimental

animals would not also operate in humans. 

Properties

Isoprene is a colorless liquid that is soluble in ethanol and diethyl

ether (Budavari 1996, HSDB 2000). Isoprene is highly flammable

and is easily ignited by heat, sparks, or flames. Vapors may form

highly explosive mixtures with air and may polymerize explosively

when heated. It is highly reactive, with reactions similar to those of

1,3-butadiene. In the absence of inhibitors, isoprene forms peroxides

upon air exposure (HSDB 2000, Saltman 1985).

Isoprene is one of the major photochemically reactive hydrocarbons

emitted by numerous plant species (Bowling et al. 1998). The large

quantities of non-methane hydrocarbons (NMHCs) emitted by

vegetation, especially in tropical and subtropical regions, influence

atmospheric processes. Isoprene and other highly reactive natural

alkenes can serve as precursors to formation of photochemical oxidants

that contribute to regional-scale air pollution (Hoffman et al. 1996).

Isoprene, the monoterpenes, and other unsaturated hydrocarbons react

with hydroxyl radicals (HO-

) and tropospheric ozone (O3) and may act

as photochemical smog precursors. The lifetime of atmospheric isoprene

has been variably estimated to be 1.3 to 34.0 hours and 1 to 2 hours

based on its rates of reactions with ozone and hydroxyl radicals

(Altschuller 1983, Guenther et al. 1995). In sunlight, ultraviolet

irradiation of isoprene, other biogenic NMHCs, and anthropogenic

hydrocarbons in the presence of atmospheric nitrogen oxide gives

numerous reaction products, including acetaldehyde, acetone, carbon

dioxide, carbon monoxide, formaldehyde, formic acid, and peroxyacetyl

nitrates (PAN). These products plus methacrolein and methyl vinyl

ketone, which are apparently specific to isoprene, represent 30 to 73%

of the carbon content of the reacted isoprene (Altschuller 1983).

Use

Approximately 95% of isoprene production is used to produce cis-1,4-

polyisoprene; 2%, to produce butyl rubber (isobutene-isoprene

copolymer); and 3%, to produce thermoplastic, elastomeric co-block

(SIS) polymers (Saltman 1985, Taalman 1996).

Production

Isoprene is recovered from C5 streams as a by-product of thermal

cracking of naphtha or gas oil. The isoprene yield is approximately 2 to

5% of the ethylene yield (Saltman 1985). U.S. demand for isoprene

grew 6.5% annually from 1985 to 1992 (CMR 1994, Chem. Week

1994). In 1994, isoprene production in the United States was

approximately 619 million lb (281,000 Mg [metric tons]) (USITC

1995), an increase of almost 29% over production in 1992 (USITC

1994). Estimated isoprene production capacity for 8 facilities was 598

million lb in 1996, based on estimates of isoprene content of product

stream available from ethylene production via heavy liquids (SRI 1997).

Chem Sources (2001) identified 24 U.S. suppliers of isoprene.

U.S. imports of isoprene (purity of 95% or more by weight) totaled

21.2 million lb in 2000 (ITA 2001). Imports for 1984 were reported to

be 11.3 million lb. In 1984, estimated U.S. exports of isoprene (purity

of 95% or more by weight) were 12.4 million lb (HSDB 2000).

Exports for 2000 increased to 37.2 million lb (ITA 2001).

Exposure

Isoprene is formed endogenously in humans and is generally the major

hydrocarbon (up to 70% in human breath) (Gelmont et al. 1981).

Concentrations in blood range from 15 to 70 nmol/L (1.0 to 4.8 μg/L)

(Cailleux et al. 1992). Humans produce isoprene endogenously at a rate

of 0.15 μmol/kg/h, equivalent to approximately 17 mg/day for a 150-lb

(70-kg) person (Taalman 1996). Endogenous production rates reported

for rats and mice are 1.9 and 0.4 μmol/kg/h, respectively (Peter et al.

1987). Ambient air concentrations of isoprene are generally less than 10

ppb or approximately 0.03 mg isoprene/m3. Based on estimated human

intake of 15 to 20 m3 air per day, ambient air would contribute less

than 0.45 to 0.6 mg/day to daily isoprene exposure. 

NIOSH collected data on potential exposure to isoprene in the

National Occupational Hazard Survey (NOHS) from 1972 to 1974

(NIOSH 1976) and in the National Occupational Exposure Survey

(NOES) from 1981 to 1983 (NIOSH 1990). The first survey (NIOSH

1976) indicated that 58,000 employees in over 30 different industries

were potentially exposed to isoprene. The more limited later survey of

six industries showed that approximately 3,700 workers were potentially

exposed to isoprene between 1981 and 1983 (NIOSH 1990).

Isoprene is emitted from plants and trees and is widely present in

the environment at low concentrations (Taalman 1996). Isoprene global

emissions, estimated at 175 to 503 million Mg per year, represent

approximately 44 to 51% of total global natural volatile organic

compound emissions (Guenther et al. 1995). The average biogenic

emission rate factor for isoprene in the United States is approximately 3

mg/m2/h. Isoprene concentrations in biogenic emissions range from 8%

to 91% of total VOCs, with a 58% average. Since isoprene biosynthesis

H2C

C

H

C

CH2

CH3
SUBSTANCE PROFILES

is associated with photosynthesis, isoprene emissions are negligible at

night (Guenther et al. 1994). The south central and southeastern areas

of the United States have the highest biogenic emissions. Summertime

isoprene emissions are highest in each region and account for more than

50% of annual biogenic emissions (Lamb et al. 1993).

Sources of anthropogenic releases of isoprene to the atmosphere

include ethylene production by cracking naphtha, wood pulping, oil

fires, wood-burning stoves and fireplaces, other biomass combustion,

tobacco smoking (3,100 μg/cigarette), gasoline, and exhaust of

turbines and automobiles (HSDB 2000).

Reported U.S. ambient air concentrations of isoprene range from

0.003 to 0.06 mg/m3 (1 to 21 ppb), with isoprene representing less than

10% of NMHCs (Arnts and Meeks 1980, Altschuller 1983, Lawrimore

and Aneja 1997, Hagerman et al. 1997). During stagnation conditions,

biogenic hydrocarbons may contribute more to total atmospheric

hydrocarbons (Altschuller 1983).

Foods of plant origin would be expected to be a source of daily

exposure to isoprene since it is emitted by agricultural crops and is the

basic structural unit in countless natural products found in foods such

as terpenes and vitamins A and K (IARC 1994). Its occurrence has

been reported in the essential oil of oranges, in the fruit of hops, and

in the root of carrots (Duke 1992).

The primary source of isoprene in indoor air is environmental tobacco

smoke. Isoprene was found to be the major component of hydrocarbons

in the air of a smoky café (10 smoking patrons, 10 not smoking) (16.7%)

and sidestream smoke (29.2%) (Barrefors and Petersson 1993). A

monitoring survey in November 1992 in homes and workplaces in the

greater Philadelphia area found mean isoprene concentrations in personal

air samples of 4.65 μg/m3 in nonsmoking homes (n = 60), 18.15 μg/m3

in smoking homes (n = 29), 5.29 μg/m3 in nonsmoking workplaces (n =

51), and 22.80 μg/m3 in smoking workplaces (n = 28). Differences in

isoprene concentrations in personal air between nonsmoking and

smoking sites were highly significant (Heavner et al. 1996). Another

survey reported median summertime isoprene concentrations of 2.90

μg/m3 in indoor air (n = 3; no information on whether occupants were

smokers or nonsmokers) compared to 0.40 μg/m3 in outdoor air (n = 1)

in the Lower Rio Grande Valley of Texas (Mukerjee et al. 1997).

Regulations

DOT

Isoprene is considered a hazardous material and special requirements have been set

for marking, labeling, and transporting this material

EPA

Clean Air Act

NSPS: Manufacture of substance is subject to certain provisions for the control of

Volatile Organic Compound (VOC) emissions

Prevention of Accidental Release: Threshold Quantity (TQ) = 10,000 lb

Comprehensive Environmental Response, Compensation, and Liability Act

Reportable Quantity (RQ) = 100 lb

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REPORT ON CARCINOGENS, ELEVENTH EDITION