In 1982¹² IARC evaluated benzene as having “sufficient evidence that benzene is carcinogenic to man,” but the available animal data on benzene as only “limited evidence of carcinogenicity in experimental animals.” This animal-data conclusion was based on:

Benzene has been tested in rats by intragastric administration and inhalation exposure, and in mice by skin application, inhalation exposure and subcutaneous injection. Oral administration to rats resulted in an increase in the incidence of Zymbal-gland carcinomas. Anaemia, lymphocytopenia and bone-marrow hyperplasia and an increased incidence of lymphoid tumours occurred in male mice exposed by inhalation to benzene; in similar inhalation studies with another strain of mice and with rats there was no evidence of a leukaemic response. Experiments involving skin application or subcutaneous injection of benzene did not produce evidence of carcinogenicity, but most of these experiments were inadequate.

The last time IARC evaluated benzene was in 1987,¹³ with evidence of carcinogenicity considered sufficient both for humans and for animals. In humans the evidence was based on increases in leukemia in benzene workers.^14,15 In animals, according to IARC

Benzene was tested for carcinogenicity in mice and rats by several routes of administration. Following its oral administration at several dose levels, it induced neoplasms at multiple sites in males and females of both species. After mice were exposed to benzene by inhalation, a tendency towards induction of lymphoid neoplasms was observed. Exposure of rats by inhalation increased the incidence of neoplasms, mainly carcinomas, at various sites. Skin application or subcutaneous injection of benzene to mice did not produce evidence of carcinogenicity, but most of the experiments were inadequate for evaluation. In a mouse-lung tumour bioassay by intraperitoneal injection, an increase in the incidence of lung adenomas was observed in males.

Near the beginning of Maltoni’s efforts evaluating benzene for carcinogenesis in animals the National Toxicology Program,^3,48–55 created by David Rall,^56,57 also embarked on unraveling the enigma of why benzene appeared to be an exception (along with arsenic^58–64) to the mammalian carcinogen paradigm^2,65–67; that is, a chemical known to cause cancer in humans had not been found to do so similarly in animals.^* In this vein, I remember being contacted persistently by industry to learn of early results of our bioassays on benzene. This was a bit amusing, because we already knew that benzene caused cancers (leukemias) in humans, and I wondered why the concentrated interest of industry in our animal findings. Calls came at least weekly from the chemical and petroleum industries. Finally one frequent caller told me that if the bioassays were negative then the industry would have some mammalian biologic means to better challenge the human epidemiologic findings, which industry was already confronting. If our bioassay were clearly negative this would help bolster their argument that other chemical exposures and workplace circumstances (confounders) would lend credence to their benzene-is-not-the-culprit rationale. In keeping with the NTP’s open policy I responded with new pathology information as it came available, reminding the inquisitors that until the data were peer-reviewed in public session, our findings could only be considered preliminary. When our pancarcinogenesis findings confirmed and complemented Maltoni’s, industry was seemingly taken aback, and momentarily puzzled regarding their next strategy.^68–70

Carcinogenesis results of 21 mutually tested chemicals including benzene were compared between the Ramazzini Foundation and the NTP, finding remarkable concordance of overall results, and identifying a combined total of 13 target sites of benzene-induced carcinogenesis in animals⁶⁷ (Table 1).

In 1928, Delore and Borgomano⁷⁸ reported the first human case of leukemia associated with benzene exposure.^2,65,78 Prior to 1928, of course, benzene was known to cause “benzene poisoning,” a sequela typically involving bone marrow damage. Chronic benzene poisoning among workers leads to various blood disorders such as leukopenia, agranulocytosis, anemia, pancytopenia, aplastic anemia, myelodysplastic syndrome (MDS; preleukemia), and leukemias.^24,79–81 More recently, occupational exposures to benzene have been causatively linked with multiple myeloma,¹⁸ non-Hodgkin’s lymphoma,²³ acute^82,83 and chronic^84–87 lymphocytic leukemia, chronic myelogenous leukemia,^82,83 and at lower exposures,^24,84,87 with some indications for lung cancer.^19–21 All of these and additional target sites have been identified in animals as well.^2,47,65,67 Another prime use of chemical carcinogenesis results allows the identification of other potential presumptive target sites that may be added to or looked for distinctly in epidemiologic investigations.

Speculatively, perhaps other sites of human carcinogenicity have not been either looked for or seen in benzene-exposed workers because death from leukemia is relatively rapid after onset and diagnosis. This could also be because available benzene cohorts individually have been small, except for the one in China. Humans showing the later-aged or latency-occurring lung cancers likely escaped developing leukemias.^{13,16,19–21} This concept of competing risks of cancer is shown experimentally quite nicely with the potent carcinogen 1,3-butadiene: as exposure concentrations are lowered different tumor patterns become manifest.^88,89 As with benzene or other chemicals, early lethal tumors such as lymphocytic lymphomas or leukemias often reduce the number of animals at risk for expressing later-developing and -occurring neoplasms at other sites. The same, of course, pertains to humans exposed to different exposure levels, patterns, and durations.

Before, at, and subsequent to Maltoni’s first reports of clear evidence of benzene carcinogenicity in laboratory animals (and arsenic as mentioned above), intense industry propaganda and pressure attempted to discount long-term animal bioassays as being irrelevant to human risk identification; this strategy certainly had much to do with stifling evidence of benzene carcinogenicity, and extended to many other economically important chemicals showing positive cancer findings in animals as well.^3,69 For some years before the benzene issue, industry and others had mounted a strenuous effort to dismiss the value of bioassays in a concerted global attempt to continue unabated marketing and use of chemicals shown to cause cancers in laboratory animals, and not yet examined epidemiologically.⁹⁰

To justify its basic premise, industry seized and campaigned on the then-notion that arsenic and benzene were both considered to be carcinogenic to humans and yet had not been shown to cause cancer in laboratory animals. Now that these two temporarily, albeit historically non-concordant chemicals have been tested adequately in animals and shown to be classic and multifarious carcinogens (benzene^2,47,65,67; arsenic^57–64), this once-dynamic duo touted by industry for vested purposes no longer serves its needs (see footnote on page 214). Now industry uses other arguments such as those based on threshold differences,⁹¹ “non-genotoxic” carcinogens,^92,93 mechanisms or “modes-of-action” being unique to animals and not relevant to humans,^91–100 even hormesis,^101,102 cell proliferation,^92,192–109 inflammation and general toxicity,^110–112 hormonal mediation,^113–115 mouse liver tumors,¹¹⁶ and benign tumors,¹¹⁷ to name a few obfuscatory issues industry has latched onto to cloud bioassay results and impede or derail regulatory actions.

Additionally, Maltoni’s first findings of benzene cancer induction in animals^40,41 were heavily disputed by industry because the organ affected by cancer was the zymbal gland (located in the inner ear canal), which humans have as a vestige. This issue of zymbal glands has been addressed and debunked, along with other so-called “rodent-unique” organs susceptible to benzene-induced carcinogenesis.¹¹⁸ Fortunately, this issue became moot given the plethora of tumors and tumor types and organ sites seen in the benzene studies. The other issue making the benzene-is-safe argument less tenable, as with arsenic, was that benzene was already long known to be carcinogenic to humans. If this had not been the case, the battle for more stringent and better worker protection and reduction of occupational standards for acceptable exposure levels would have been even more difficult. As it was, lowering of the occupation exposure standard took ten years longer than anticipated because of adverse decisions issued by the U.S. Supreme Court.¹¹⁹