This issue of “In Focus” focuses on the results of the above-mentioned study, published in March this year by the International Agency for Research on Cancer (IARC) as Monograph Volume 138.
The IARC is the specialized cancer agency of the World Health Organization. The objective of IARC is to promote international collaboration in cancer research.
The Agency is interdisciplinary, bringing together skills in epidemiology, laboratory sciences, and biostatistics to identify the causes of cancer so that preventive measures may be adopted and the burden of disease and associated suffering reduced. A significant feature of the Agency is its expertise in coordinating research across countries and organizations; its independent role as an international organization facilitates this activity. IARC has a particular interest in conducting research in low- and middle-income countries through partnerships and collaborations with researchers in these regions.
In February–March, 2025, a Working Group of 20 scientists from 16 countries met at the IARC in Lyon, France, to finalise their evaluation of the carcinogenicity of automotive gasoline and some oxygenated gasoline additives.
The MTBE assessment in the IARC study is based on numerous, comprehensive studies. Conclusive evidence from these studies supports the position that “MTBE, ETBE and TBA are unlikely to be a carcinogenic hazard in humans”.
In its final evaluation the IARC study classified automotive gasoline as “carcinogenic to humans” (Group 1). While other oxygenates were each evaluated as “not classifiable as to its carcinogenicity to humans” (Group 3), MTBE and ETBE were classified as “possibly carcinogenic to humans” (Group 2B). Overall, the IARC study concludes that the risk of carcinogenicity from oxygenated gasoline additives for consumers is unlikely.
The Asian Clean Fuels Association feels proud to present another scientific report from a highly reputable health organization, which shows no significant health impact is being caused by the use of MTBE and other ethers in gasoline. The IARC report follows numerous risk assessment in the EU and China, as well as other scientific studies conducted elsewhere, none categorizing MTBE as “carcinogenic to humans” (Group 1).
Based on the findings of the report, gasoline producers, blenders as well consumers can fully focus on the advantages that fuel ethers provide, contributing significantly to cleaner and less polluted air and a healthier environment for humanity.
The Working Group assessments were published in Volume 138 of the IARC Monographs, which can be found on https://monographs.iarc.who.int/news-events/volume-138-automotive-gasoline-and-some-oxygenated-gasoline-additives/
In its evaluation automotive gasoline was classified as “carcinogenic to humans” (Group 1) based on “sufficient” evidence for cancer in humans, and the combination of “sufficient” evidence for cancer in experimental animals and “strong” mechanistic evidence in exposed humans. Methyl tert-butyl ether (MTBE) and ethyl tert-butyl ether (ETBE) were each classified as “possibly carcinogenic to humans” (Group 2B) based on “sufficient” evidence for cancer in experimental animals and also (for ETBE) “strong” mechanistic evidence in experimental systems. tert-Butyl alcohol (TBA), diisopropyl ether (DIPE), and tert-amyl methyl ether (TAME) were each evaluated as “not classifiable as to its carcinogenicity to humans” (Group 3).
The IARC report explains that MTBE, ETBE, TBA, TAME, and DIPE are volatile compounds used as oxygenated additives in gasoline to increase combustion efficiency, especially since the elimination of lead. All except TAME are listed as high-production-volume chemicals. MTBE and ETBE have been used most widely as gasoline additives, at concentrations up to 15% and 22%, respectively. Although no longer added to gasoline in the USA, MTBE and ETBE are currently used in Europe, Asia, and elsewhere. Workers can be exposed during additive production or via gasoline vapours containing these additives. Occupational exposure has been measured in ship and railroad tanker workers, gasoline pump repairers and inspectors, service station attendants, and automobile mechanics. The general population is mainly exposed via gasoline vapours at service stations, via air pollution, or via water and soil contaminated by gasoline spills.
The IARC MTBE assessment is based on numerous studies, summarized in a ScienceDirect toxicology research (link) as:
“Systematic evaluation of the evidence base on methyl tert-butyl ether supporting a lack of concern for carcinogenic hazard in humans based on animal cancer studies and mechanistic data”
The report states and concludes that
The report highlights that MTBE is a high-octane fuel component that helps gasoline burn cleaner and reduces automobile emissions. In 1999, the IARC categorized MTBE as “not classifiable” regarding human carcinogenicity.
Since then, additional studies have been published that substantially added to the evidence base to examine the carcinogenic potential of MTBE in humans. A systematic literature search and review was conducted to identify mechanistic data, as well as studies investigating cancer in MTBE-exposed humans and experimental animals. Critical appraisal was performed for relevant studies with mechanistic data organized and evaluated within Key Characteristics of Carcinogens (KCCs). Three standard animal cancer bioassays showed a low incidence of hepatocellular adenomas in female mice (inhalation exposure), with renal adenomas/carcinoma (inhalation) and brain tumours (drinking water) in male rats exposed to high concentrations of MTBE. Evidence extracted from the literature demonstrate that the mechanism of male rat renal tumours does not operate in humans. Review of the strength of mechanistic data was based on activity, relevancy, and reliability, with information-dense KCC2—is genotoxic, and KCC10—alters cell proliferation, cell death, and nutrient supply, together supporting that MTBE is unlikely to be a carcinogenic hazard to humans.
All available evidence, based on general principles and procedures described by the IARC Preamble (2019) for conducting cancer hazard evaluations, was evaluated in a systematic review. This included epidemiological, experimental animal, and mechanistic data such as absorption, distribution, metabolism and excretion (ADME) data, mechanistic data for KCCs (Smith et al., 2016), and information on any emerging carcinogen mechanisms (IARC Preamble, 2019). Methods used for assessing and integrating mechanistic data were based on biological pathway-based concepts described by Smith et al. (2016) and Wikoff et al. (2019). Outcomes, such as tumour formation, observed in animal and human studies were considered in the assessment as described by the WHO IPCS (Meek et al., 2014, Meek and Wikoff, 2023).
The comprehensive search and screening of the evidence identification was followed by the appraisal of the data extraction and quality and the synthesis and identification of the data, according to the IARC preamble, which led to the “conclusion for strength of data integrated within and across evidence streams for assessing human carcinogenic hazard”.
A total of 2409 citations were screened for relevancy from the initial literature search in February 2024. An additional 14 papers were identified from hand-searching giving a total of 2423 publications.
Of these, 136 publications were retrieved and reviewed for relevance at the full-text level. The updated literature searches conducted in November 2024 and January 2025 resulted in identification of 2 recently published studies. No relevant human cancer studies were identified in the initial search, however, one relevant human cancer study was identified in the updated literature search conducted in November 2024 along with one mechanistic study in the literature search conducted on January 21, 2025. Overall, five studies in experimental animal models evaluated cancer outcomes associated with MTBE exposure. Another 73 articles contained mechanistic data, and 25 articles reported emerging carcinogenic mechanisms related to obesity, type-II diabetes, and/or insulin resistance.
In this systematic review of MTBE’s evidence base associated with carcinogenic activity, one human study, five experimental animal cancer studies, along with a significant volume of mechanistic data mapped across the KCCs was reviewed to assess the potential of MTBE’s carcinogenic hazard in humans. Following data integration with animal models and mechanistic data such as ADME and for KCCs, the conclusion reached is that MTBE is unlikely to be a carcinogenic hazard in humans.
Based on the integration of reliable studies and endpoint methodology, three standard experimental animal studies, along with mechanistic data organized, evaluated, and integration across ten KCCs was considered to inform the human carcinogenic potential of MTBE. Although a low, and non-reproducible tumour incidence was identified in three standard reliable cancer studies, MTBE’s lack of genotoxic activity and with limited strength of activity across the other KCCs does not support concern for carcinogenic activity in humans.
As such, a biologically plausible mechanism leading to carcinogenic activity of MTBE that would operate in humans is not evident within this significant evidence base supported mainly by animal in vivo studies.
In this issue of our “In Conversation with” we talked to Mr. Jeff Hove, acting Vice President and Executive Director at the Fuels Institute. In recent years we have seen some initiatives to consider policies to ban the sale of vehicles equipped with internal combustion engines (ICE), predominantly emerging in Europe, but also spreading out in parts of Asia.
In this issue of our “In Conversation with” we talked to Dr Tilak Doshi, an energy sector consultant based in Singapore. Dr Doshi shared his views and observations about the global “2050 decarbonisation” plan and move towards Electric Vehicles (EVs) with us. We would like to thank Dr Doshi for his efforts to comprehensively answer our questions which provide some highly valuable and very interesting insights into this matter, highlighting a range of topics often overlooked in the political discussion between the various stakeholders in the race to save the world from impending climate catastrophe.
In this issue of our “In Conversation with” we talked to Dr Sanjay C Kuttan, Chairman of the Sustainable Infrastructure Committee at Sustainable Energy Association of Singapore (SEAS).
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