Methyl-tertiary-butyl-ether (MTBE) misclassified.

Methyl-tertiary-butyl-ether (MTBE) was introduced into motor fuels in 1992 to reduce carbon monoxide automotive emissions in areas where the National Ambient Air Quality Standards for CO were exceeded. At a meeting of the National Toxicology Program's Board of Scientific Counselors (2-3 December 1998), data were presented showing that exposure to MTBE caused increased incidence of liver tumors, renal adenomas, carcinomas and interstitial cell adenomas of the testes in male, and lymphomas and leukemia in female CD1 mice [National Toxicology Program, 1998]. Despite this evidence, the NTP Board defeated a motion to list MTBE as "Reasonably anticipated to be a human carcinogen" by a vote of 6 to 5. This decision directly contravenes rules and procedures previously established by NTP for assessing carcinogenicity of chemical compounds. Good public health policy dictates that the NTP Board conduct another review of MTBE with proper consideration of the criteria that have been established for listing agents as carcinogens. Millions of Americans who are exposed daily to this chemical deserve an unbiased evaluation of carcinogenic agents being introduced into the environment.

Dangerous and cancer-causing properties of products and chemicals in the oil-refining and petrochemical industry--Part XXII: Health hazards from exposure to gasoline containing methyl tertiary butyl ether: study of New Jersey residents.

Methyl tertiary butyl ether has caused the following cancers in rats and mice: kidney, testicular, liver, lymphomas, and leukemias. Thus, in the absence of adequate data on humans, it is biologically plausible and prudent to regard methyl tertiary butyl ether-for which there is sufficient evidence of carcinogenicity in experimental animals-as a probable human carcinogen. This means that some humans are at extreme risk of contracting cancers resulting from their exposure to oxygenated gasoline containing methyl tertiary butyl ether. Immediately after the introduction of methyl tertiary butyl ether into gasoline, many consumers of this product in New Jersey, New York, Alaska, Maine, Pennsylvania, Colorado, Arizona, Montana, Massachusetts, California, and other areas, experienced a variety of neurotoxic, allergic, and respiratory illnesses. These illnesses were similar to those suffered by refinery workers from the Oil, Chemical, and Atomic Workers Union who mixed methyl tertiary butyl ether with gasoline. Additionally, these illnesses occurred following exposure to extremely low levels of methyl tertiary butyl ether in gasoline, particularly when compared to the adverse health effects that occurred only after exposure to very high levels of conventional gasoline. Thus, gasoline containing methyl tertiary butyl ether exhibited substantially more toxicity in humans than gasoline without this additive. A number of oil industry-sponsored or influenced reports alleged that these illnesses were either unrelated to exposure to reformulated gasoline or were characteristic of some yet-to-be-identified communicable disease. These studies further alleged that the widespread concern was not about illness, but was merely a reaction to the odor and the five cent increase in the price of gasoline. To clarify the significance of this issue, it is important to note that consumers have been using gasoline for many decades, with complaints only occurring following exposure to high levels at 100s ppm or higher. After the introduction of methyl tertiary butyl ether gasoline there were thousands of human health complaints. The sudden increase in widespread illnesses from which many thousands of individuals throughout the United States began to suffer immediately following the introduction of methyl tertiary butyl ether into gasoline provides strong and unquestionable evidence that gasoline containing methyl tertiary butyl ether is associated with human illnesses. When considering the severity of the illnesses in humans, it is prudent that this highly dangerous chemical be promptly removed from gasoline and comprehensive studies be conducted to assess the long-term effects that human may experience in the future from past and current exposure.

Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry. VIII. Health effects of motor fuels: carcinogenicity of gasoline--scientific update.

1. Significant increases in tumors of kidney, liver, and other tissues and organs following exposure to gasoline provide sufficient evidence of carcinogenicity. 2. Benzene, a significant component of gasoline, has been established without question as a human carcinogen by IARC, EPA, and WHO. 3. 1,3-Butadiene, a component of gasoline, is a powerful carcinogen in both animals and humans. 4. Sufficient evidence for the carcinogenicity of alkyl benzenes, very significant components of gasoline, has also been established. 5. Human epidemiologic studies show important increases in cancers of the kidney, stomach, brain, pancreas, prostate, lung, and skin as well as hematopoietic and lymphatic leukemias as a result of exposure to gasoline, its components, and its vapors. 6. Stage 2 controls are being implemented to reduce exposure of the human population to gasoline vapors.

Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry: Part I. Carcinogenicity of motor fuels: gasoline.

Studies in humans and animals have shown that gasoline contains a number of cancer-causing and toxic chemicals such as 1,3-butadiene, benzene, toluene, ethylbenzene, xylenes, isoparaffins, methyltert-butylether, and others. The International Agency for Research on Cancer (IARC) in its Monograph Supplement 7 (1987) concludes that "in the absence of adequate data on humans, it is biologically plausible and prudent to regard agents for which there is sufficient evidence of carcinogenicity in experimental animals as if they present a carcinogenic risk to humans." Epidemiological studies in humans provide important evidence of potential increased risk of leukemia, lymphatic tissue cancers, cancers of the brain, liver, and other organs and tissues. Recently (July, 1990) the American Conference of Governmental Industrial Hygiene (ACGIH) recommended that the TLV-TWA for benzene be reduced from 1 ppm to 0.1 ppm (ACGIH, 1990). The Collegium Ramazzini and others have also recommended that the exposure level for 1,3-Butadiene be reduced from 1,000 ppm to below 0.2 ppm. This recommendation is based on the findings that were presented at the Symposium on Toxicology, Carcinogenesis, and Human Health Aspects of 1,3-Butadiene (Environ. Health Perspec., 1990). Thus, studies on health effects resulting from very low levels of benzene, 1,3-butadiene, and other cancer-causing chemicals--components of gasoline--necessitate that all avoidable exposure to gasoline or gasoline vapors be avoided.

Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry--Part II: Carcinogenicity, mutagenicity, and developmental toxicity of 1,3-butadiene.

1,3-butadiene (BD) is present in synthetic rubber and motor fuels (gasoline). BD is shown to cause lymphocytic lymphomas, heart hemangiosarcomas, lung alveolar bronchiolar cancers, forestomach-squamous cell cancers, harderian gland neoplasms, preputial gland adenoma or carcinoma, liver-hepatocellular cancers, mammary gland acinar cell carcinomas, ovary-glanulosa cell carcinoma, brain cancers, pancreas adenoma and carcinoma, testis-Leydig cell tumors, thyroid follicular adenoma and carcinoma, and zymbal gland carcinoma in rodents and to date no exposure level has been established at which this chemical does not cause cancers. In humans BD causes increase in lymphomas, leukemias, and other cancers of hematopoietic systems and organs. BD is also a potent alkylating agent, directly toxic to developing embryos and damages progeny after parental exposure.

Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry: Part V--Asbestos-caused cancers and exposure of workers in the oil refining industry.

In the oil refining and petrochemical industries exposure to cancer-causing asbestos particles, especially during equipment repair and maintenance, is very high. Up to 90% of workers in the oil refining industry had direct and/or indirect contact with asbestos, and more than half of this contact occurred without the use of any kind of precaution, thus these workers are in high risk of developing lung cancer and mesothelioma, both fatal diseases. The hazards include: inadequate health and safety training for both company personnel and workers, failure to inform about the dangers and diseases (cancers) resulting from exposure to asbestos; excessive use of large numbers of untrained and uninformed contract workers; lack of use of protective equipment; and archaeological approaches and responses to repairing asbestos breaks and replacement of asbestos in oil refining facilities. For a better understanding of practices and policies in the oil refining industry, refer to Rachel Scott's Muscle and Blood, in particular the chapter "Oil" (E.P. Dutton, New York, 1974), as well as to an editorial which appeared in the Oil and Gas Journal, April, 1968.

Benzene health effects: unanswered questions still not addressed.

Data which could have helped answer many of the scientific questions posed in 1983 concerning the carcinogenicity of benzene are not yet available. Since we do not know of any safe level above zero, the problems that have been plaguing the health protection process relative to benzene can perhaps be best resolved by setting current recommended maximum levels of exposure to 0.004 to 0.1 ppm, and, to the extent possible, avoiding any exposure at all to benzene and benzene-containing products.

Dangerous properties of petroleum-refining products: carcinogenicity of motor fuels (gasoline).

Gasoline contains large numbers of dangerous and cancer-causing chemicals such as benzene, butadiene, toluene, ethylbenzene, xylene, trimethyl pentane, methyltertbutylether (MTBE) and many others. For the U.S. alone approximately 140 billion gallons of gasoline were consumed in 1989. An increase in only ten cents per gallon in price of gasoline generates 14 billion dollars in extra profit per year for oil industry cartel. Laboratory animals exposed to gasoline developed cancers in different tissues and organs. A number of epidemiological studies in humans provide evidence of increased cancer risk of leukemia, kidney, liver, brain, lymphosarcoma, lymphatic tissue pancreas and other tissues and organs.

A report on methods to reduce, refine and replace animal testing in industrial toxicology laboratories.

The Committee to Promote Principles of Reduction, Refinement and Replacement of Animal Testing in Industrial Toxicology Laboratories was established in 1987 to work toward industrywide improvements in laboratory animal testing methods. The committee's goals are to gather information about effective nonanimal testing techniques and other methods of conserving and improving the care of laboratory animals, to work toward the systematic validation of nonanimal alternatives, and to disseminate useful information about progressive programs and policies throughout the industrial toxicology community. This is the first in a continuing series of reports the committee plans to produce as part of an ongoing program to promote communication among industrial toxicologists about successful methods of reducing, refining and replacing animal testing. Here are some of the report's major findings: (1) Animal care and use committees charged with the oversight of laboratory animal use are a universal practice at the companies surveyed. (2) Significant reductions in the number of animals used for acute toxicity testing have taken place at all the companies during the last 5- to 10-year period. (3) Structure-activity relationships (predicting a test compound's properties based on the known properties of familiar chemicals with similar structures) are widely used to minimize, but not replace, the use of animals. (4) Tissue and organ culture systems are being used with increasing frequency for screening and mechanistic studies, but are not completely replacing animal evaluations as a final step. (5) There is a pressing need for the systematic and scientifically sound validation of nonanimal alternative techniques to reduce the use of animals in toxicology testing while satisfying requirements for the protection of public safety.

A method for in vitro culture of rat Zymbal gland: use in mechanistic studies of benzene carcinogenesis in combination with 32P-postlabeling.

Zymbal glands were excised bilaterally from the ear ducts of female Sprague-Dawley rats (three/group), minced into approximately four fragments per gland, and transferred into a microtiter plate containing 1.5 mL per well of Waymouth's tissue culture medium supplemented with fetal calf serum, hydrocortisone, insulin, and gentamicin. After addition of a test compound or solvent vehicle, plates were incubated for 6, 24, 48, or 96 hr at 37 degrees C in a humidified atmosphere of 5% CO2 in air. Tissue in culture for 6 hr was histologically indistinguishable from the freshly excised tissue, while that in culture for 24, 48, and 96 hr showed a progressive deterioration often with necrosis and/or squamous metaplasia. More pronounced deterioration was noted in samples treated with 750 or 1500 micrograms/mL of benzene. Using a nuclease P1-enhanced 32P-postlabeling assay, aromatic DNA adducts were detected in cultured Zymbal glands exposed for 48 hr to benzene and its derivatives, as well as to 7,12-dimethylbenzanthracene (DMBA) and 2-acetylaminofluorene (AAF). Benzene produced very low levels of adducts (0.5 adducts per 10(9) nucleotides), whereas its congeners produced relatively high levels of adducts (50-2000 lesions per 10(9) nucleotides), which decreased in the order benzoquinone greater than hydroquinone greater than phenol greater than benzenetriol greater than catechol. Each adduct profile overall was characteristic for the compound studied, suggesting the formation of compound-specific electrophiles. AAF and DMBA adducts were identical to those formed in vivo in animals. Our results show that the Zymbal glands are capable of metabolizing different carcinogens to DNA-reactive intermediates, a process that may be causally associated with tumor formation in vivo in this organ.

Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic.

32P analysis of DNA adducts in tissues of benzene-treated rats.

Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, liver, and mammary gland of Sprague-Dawley rats following chronic, high-dose administration of benzene. The carcinogenic activity of benzene is thought to be caused by activation to toxic metabolites that can interact with DNA, forming covalent adducts. A nuclease P1-enhanced 32P-postlabeling assay, having a sensitivity limit of 1 adduct in 10(9-10) DNA nucleotides, was found suitable for measuring aromatic DNA adducts derived in vitro from catechol, benzenetriol (BT), phenol, hydroquinone (HQ), and benzoquinone (BQ), potential metabolites of benzene. When DNA specimens isolated from tissues of female Sprague-Dawley rats at 24 hr after an oral gavage dose of 200 to 500 mg/kg, 5 days/week, in olive oil (3 mL/kg) for 1 day, 1 week, 5 weeks, and 10 weeks were analyzed by the 32P-postlabeling procedure, no aromatic adducts were detected unequivocally with DNA samples of liver, kidney, bone marrow, and mammary gland. With Zymbal gland DNA, three weak spots at levels totaling four lesions per 10(9) DNA nucleotides were seen only after 10 weeks of treatment, and these adducts did not correspond chromatographically to major adducts in vitro from the above specified compounds. Consequently, this finding requires confirmatory experiments. This distinct adduct pattern may relate to tumor induction in this organ following benzene administration. Our results also indicate that DNA adducts derived from catechol, BT, phenol, HQ, and BQ are either not formed in vivo with benzene or formed at levels below the detection limit of 1 adduct per 10(9-10) DNA nucleotides.

Developmental toxicity of Clarified Slurry Oil applied dermally to rats.

Clarified Slurry Oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 pregnant rats at doses of 0, 4, 8, 30, 125, and 250 mg/kg/day. All groups received the test material on gestation days 0-19. CSO was applied undiluted and left uncovered on the skin; collars were placed on the rats to minimize ingestion of the test material. Signs of maternal toxicity, some of which were seen at dose levels as low as 8 mg/kg/day, included vaginal bleeding, decreased body weight gain, reduced food consumption, death, increased relative liver weights, atrophy of the thymus, and aberrant serum chemistry. The number of fetal resorptions/deaths was markedly increased and the number of viable offspring decreased by CSO at dosages of 30 mg/kg/day and above. The group receiving 250 mg/kg/day carried no viable offspring. Fetuses from pregnant females exposed to CSO at dose levels in excess of 8 mg/kg/day were smaller than those from control and 4 mg/kg/day groups, and their skeletons showed decreased ossification. Abnormal external development and visceral development were observed in living and dead fetuses exposed in utero to CSO at dose levels as low as 8 mg/kg/day. Based on these data, 4 mg/kg/day represents the No-Observed-Adverse-Effect-Level for both maternal and developmental toxicity.