National Toxicology Program

National Toxicology Program
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Abstract for TR-486 - Isoprene (CASRN 78-79-5)

ABSTRACT

Toxicology and Carcinogenesis Studies of Isoprene (CAS No. 78-79-5) in F344/N Rats (Inhalation Studies)

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Chemical Formula: C5H8

Isoprene, the monomeric unit of natural rubber and naturally occurring terpenes and steroids, is primarily obtained as a by-product of naphtha cracking for ethylene production. It is emitted from plants and trees, has been detected in tobacco smoke and automobile exhaust, and was identified as a major endogenous hydrocarbon in human breath. Isoprene was selected for toxicologic evaluation because of its structural similarity to 1,3-butadiene, a potent, multi-organ, rodent carcinogen, and the potential for human exposure due to its large annual production volume. A previous 26-week inhalation study followed by a 26-week recovery period provided clear evidence of carcinogenic activity of isoprene in male B6C3F1 mice. A similar study in male F344/N rats was inconclusive. Male and female F344/N rats were exposed to isoprene (99% pure) by whole body inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow and peripheral blood cells, and rat lung fibroblasts.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female F344/N rats were exposed to 220, 700, or 7,000 ppm isoprene by inhalation, 6 hours per day, 5 days per week, for 105 weeks.

Survival and Body Weights 
Survival rates and mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study.

Urinary Vinyl Lactic Acid ; Biomarker of Exposure 
At 3, 6, 12, and 18 months, the concentrations of vinyl lactic acid normalized to creatinine in the urine increased with increasing exposure concentration in all exposed groups of male and female rats; however, these increases were not proportional to isoprene exposure concentrations, indicating nonlinear metabolism over this range of exposure concentrations.

Pathology Findings
Exposure-related increases in the incidences of mam mary gland fibroadenoma were observed in male rats in all groups. The incidences of fibroadenoma in 7,000 ppm males and in all groups of exposed females were significantly greater than those in the chamber control groups. The incidences of fibroadenoma in all exposed groups of males and females and of multiple fibroadenoma in 7,000 ppm males and in all groups of exposed females exceeded the historical control ranges. In addition, the finding of mammary gland carcinoma in exposed male rats was noteworthy because this neoplasm rarely occurs in control male rats.

The incidences of renal tubule adenoma in 700 and 7,000 ppm males and of renal tubule hyperplasia in 7,000 ppm males were significantly greater than those in the chamber controls. The severity of kidney nephropathy was slightly increased in 7,000 ppm males when compared to chamber controls.

An exposure-related increase in the incidences of interstitial cell adenoma of the testis was observed in male rats. The incidences of bilateral interstitial cell adenoma and of unilateral and bilateral interstitial cell adenoma (combined) of the testis in 700 and 7,000 ppm males were significantly greater than those in the chamber controls. The incidences of interstitial cell adenoma in 700 and 7,000 ppm males exceeded the historical control range.

Several rare neoplasms including benign astrocytoma, malignant glioma, malignant medulloblastoma be nign meningeal granular cell tumor, and meningeal sarcoma were observed in the brain of exposed female rats. These neoplasms have seldom or never occurred in historical chamber controls.

The incidences of splenic fibrosis in 700 and 7,000 ppm males were significantly greater than that in the chamber control group.

GENETIC TOXICOLOGY

Isoprene was not mutagenic in S. typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. The cell cycle duration of proliferating bone marrow cells of mice exposed to 7,000 ppm isoprene was significantly lengthened. No increases in the frequency of chromosomal aberrations were observed in bone marrow cells of male mice after 12 days of exposure to isoprene, and lung fibroblasts of male and female rats exposed to isoprene for 4 weeks showed no increase in the frequency of micronuclei.

CONCLUSIONS

Under the conditions of this 2-year inhalation study, there was clear evidence of carcinogenic activity of isoprene in male F344/N rats based on increased incidences of mammary gland fibroadenoma and carcinoma, renal tubule adenoma, and testicular interstitial cell adenoma. There was some evidence of carcinogenic activity of isoprene in female F344/N rats based on increased incidences and multiplicity of mammary gland fibroadenoma. A low incidence of rare brain neoplasms in exposed female rats may have been due to exposure to isoprene.

Exposure to isoprene by inhalation for 2 years resulted in increased incidences of renal tubule hyperplasia and splenic fibrosis in male rats.

Synonyms: Isopentadiene; b-methylbivinyl; 2-methyl-1,3-butadiene
 




2-Year Carcinogenesis Studies of Isoprene

 

Male
F344/N Rats

Female
F344/N Rats

Concentrations in air

0, 220, 700, or 7,000 ppm

0, 220, 700, or 7,000 ppm

Body weights

Exposed groups similar to chamber control group

Exposed groups similar to chamber control group

Survival rates

18/50, 16/50, 15/50, 15/50

29/50, 30/50, 28/50, 27/50

Nonneoplastic effects

Kidney: renal tubule hyperplasia (standard evaluation - 0/50, 2/50, 6/50, 8/50; standard and extended evaluations combined - 7/50, 6/50, 13/50, 18/50)

Spleen: fibrosis (11/50, 14/50, 24/50, 22/50)

None

Neoplastic effects

Mammary gland: fibroadenoma, multiple (1/50, 1/50, 0/50, 7/50); fibroadenoma, including multiple (2/50, 4/50, 6/50, 21/50); carcinoma (0/50, 1/50, 1/50, 2/50)

Kidney: renal tubule adenoma (standard evaluation - 0/50, 2/50, 2/50, 6/50; standard and extended evaluations combined - 2/50, 4/50, 8/50, 15/50)

Testis: interstitial cell adenoma, bilateral (20/50, 29/50, 37/50, 48/50); interstitial cell adenoma, including bilateral (33/50, 37/50, 44/50, 48/50)

Mammary gland: fibroadenoma, multiple (7/50, 12/50, 19/50, 17/50);

fibroadenoma, including multiple (19/50, 35/50, 32/50, 32/50)

Uncertain findings

None

Brain: benign astrocytoma (0/50, 0/50, 1/50, 0/50); malignant glioma (0/50, 0/50, 0/50, 1/50); malignant medulloblastoma (0/50, 0/50, 0/50, 1/50); meninges, benign granular cell tumor (0/50, 1/50, 0/50, 1/50); meninges, sarcoma (0/50, 1/50, 0/50, 1/50)

Level of evidence of carcinogenic
activity

Clear evidence

Some evidence

Genetic Toxicology of Diisopropylcarbodiimide
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA98, TA100, TA1535, and TA1537 with and without S9
Sister chromatid exchanges Cultured Chinese hamster ovary cells in vitro: Negative with and without S9
Sister chromatid exchanges Mouse bone marrow in vivo: Positive
Chromosomal aberrations Cultured Chinese hamster ovary cells in vitro: Negative with and without S9
Chromosomal aberrations Mouse bone marrow in vivo: Negative
Micronucleated erythrocytes Mouse peripheral blood in vivo: Positive
Micronucleated erythrocytes Lung fibroblasts: Negative

Report date: July 1999

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies


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