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Recent News in Benzene and Hematopoietic Malignancies

By Nachman Brautbar, M.D.

Dosimetry of Benzene Exposure
Several factors are to be taken into account when assessing benzene-induced hematopoietic malignancies. Among these factors (not inclusive of all factors): a) susceptibility of an individual1; b) dose-intensity of exposure; and c) cumulative exposure. For the majority of epidemiological studies, only cumulative exposure dosimetry has been considered. The role of intensity of exposure and peak exposure levels was demonstrated as early as the 1980s. Indeed, Snyder et al. demonstrated that intermittent administration of benzene to mice resulted in the same cancer response as that of continuous administration of a higher benzene dose.2 The epidemiological study by Gun et al (2000) demonstrated an increased leukemia incidence based on intensity of benzene exposure, emphasizing the importance of intensity of benzene exposure.3 Based on intensity of benzene exposure, the authors reported that those workers who had high intensity exposure between 3.49 - 4.8 parts per million (ppm) had a 26-fold increased risk of leukemia. The observations from this study indicate that intermittent intense peak benzene exposure carries the same risk of cumulative benzene exposure, and based on the study of Atkinson et al (2001) even greater risk compared with cumulative exposure to benzene.4 Indeed, the study by Glass et al5 has further demonstrated the importance of intensity of exposure in benzene dosimetry.

Low Levels of Benzene Exposure and Hematopoietic Malignancies
The study by Glass et al demonstrated that exposure intensity in the highest exposed job was strongly related to leukemia risk, with the increased risk starting at around 0.8 - 1.6 ppm.5 Expressed as cumulative ppm-years, Glass et al. demonstrated increased leukemia risk greater than 2 ppm-years. The study further concludes that:

"It has been suggested that there might be "no increased risk" at cumulative exposures below 200 ppm-years or intensity of less than 20-60 ppm. In a recent large cohort study of Chinese workers, the relative risk for all hematologic neoplasms was 2.2 (95% [confidence interval] CI 1.1 - 4.2) for workers exposed to benzene at estimated average levels of less than 10 ppm. The Glass study demonstrates that the risk of leukemia was increased at all cumulative exposures above 1 ppm-year, with a strong exposure–response relationship, with no evidence of a threshold."5

The most recent study by Lan et al6 further supports the observation of Glass et al5 and Hayes et al.7 Lan et al showed that white blood cell counts and cell colony progenitive cell formation were substantially affected at levels of 1 ppm of benzene or less. Mehlman8, in a recent review, examined leukemia risk in light of the Glass study and Occupational Safety and Health Administration's (OSHA) risk estimates and determined that the increased risk translated to 16 parts per billion. In the most recent paper of Glass et al., the authors revisit their previous study and included occasional high exposures (intensity) as result of spillages.9 The authors concluded that the data demonstrates as strong association between benzene exposure at intensity levels of 0.8 ppm and 16 ppm-years cumulative exposure. The 0.8 ppm intensity exposure is in line with the analyses of Mehlman and Lan et al. These studies indicate that intensity of exposure at levels as low as 0.8 ppm are of equal or more toxic as compared to cumulative exposure and provide a strong basis for disagreement with the notion of "risk is increased only at 200 ppm or more".

Gasoline: A Hematopoietic Carcinogen
Gasoline contains benzene, depending on the source of gasoline, and countries, ranges of concentration of benzene in gasoline have been reported as 1-6%. Gasoline is also used as an industrial solvent and workers commonly experience inhalation and skin exposure. In my practice, it is not unusual to hear from workers that "I washed my hands with gasoline to remove paint daily" or "the smell was so strong that I got dizzy", demonstrating substantial exposure to gasoline ongoing on a daily basis. Since benzene is a known human carcinogen, it would be expected that gasoline will be also a hematopoietic toxic and cancer causing agent as well. Indeed, Aksey et al10 as early as 1928 reported aplastic anemia, and in 1941, Machele et al11 reported thrombocytopenia from gasoline intoxication. Other hematopoietic malignancies have been reported as a result of gasoline exposure.

Epidemiological studies of workers and filling station attendees have shown genotoxic effects at very low benzene from gasoline vapor exposure.12,13,14,15 Brandt et al have demonstrated genotoxic effects in workers exposed to low levels of benzene from gasoline.16 Santos-Mello et al have shown chromosomal deletions in lymphocytes of workers exposed to gasoline as attendants.13 Infante et al reported hematopoietic malignancy in petrol exposed workers. Similar exposures to gasoline in garage mechanics and filling stations have been reported.17

Acute leukemia has been described in petrol stations and gasoline station attendants.18,19,20 There is clear scientific demonstration that gasoline containing benzene is a hematopoietic toxin, as gleaned from the studies described in this manuscript. That benzene exposure from gasoline, described by some as "low level" is associated with hematopoietic cell damage, is supported by the most recent studies by Lan et al6 showing human lymphocyte changes in benzene exposure to less than one part per million, and with studies of DNA breaks and changes, in experimental animals exposed to as low as 40 parts per billion and 100 parts per billion.22,23

That gasoline containing benzene is hematotoxic not only on an occupational basis, but also on an environmental basis is supported by observations from a recent study entitled "Risk of Cancer as a Result of Community Exposure to Gasoline Vapors" published in Archives of Environmental Health, October 2004, by Patel et al.23 The authors of this study examined the effect of underground petroleum gasoline storage leaking tanks on a surrounding population. The risk of cancer was examined. Benzene exposure levels were described as low levels for a period of 10 years, in the plume of water. The study found a statistically significant increased risk of leukemia in this population group, at low level of benzene from a gasoline spill. The study of this population is similar to a study by Lindstrom et al, who found benzene concentration of .8 to 1.7 parts per million within a shower stall of the household using gasoline contaminated ground water.24 This recent population study further supports the carcinogenicity of gasoline containing benzene in line with the experimental animal studies, and human studies.6,8,9,22,23

It is true that there are some papers published by various individuals and bodies describing benzene in gasoline as "safe". Putting aside "agendas", the Federal Manual on Scientific Evidence, 2000, clearly recognizes that one can find equally qualified and well credentialed experts who may reach opposite opinions with regard to the same chemical. (I want to believe that those who discount benzene in gasoline as a carcinogen are indeed free of any "agenda"). Nevertheless, the findings of carcinogenicity from gasoline raises legitimate concerns and industry physicians examining patients on an occupational basis as well as a non-occupational basis in private practice, should be educated and sensitive with regard to taking a detailed history of exposure to both industrial and non-industrial carcinogens. Commonly, physicians who have not taken an occupational and non-occupational exposure history, or simply are not educated in the field, will lump a diagnosis as "idiopathic". Idiopathic to them, but not idiopathic to medical science and literature. We have seen too frequently "idiopathic" when a private practice physician did not even ask about exposure history.

Bullet points:

  1. Intensity and peak exposures.
  2. Benzene carcinogenicity at levels below 1 ppm.
  3. Gasoline containing benzene carcinogenicity.

Disclosure
This review paper is a short excerpt, and does not purport to be presented as a comprehensive review of the literature.

References

  1. American Petroleum Institute. Toxicological Review on Benzene. API Toxicological Review. Benzene. September 1948.
  2. Snyder CA, Sellakumar AR, James DJ, et al. The carcinogenicity of discontinuous inhaled benzene exposures in CD-1 and C57Bl/6 mice. Arch Toxicol. 1988;62(5):331-5.
  3. Gun R, Pilotto L, Ryan P, et al. Health Watch: the Australian Institute of Petroleum Health Surveillance Program. Eleventh Report. The University of Adelaide. Australia. 2000.
  4. Atkinson S, Coppock J, Fritschi L, et al. Lympho-haematopoietic cancer and exposure to benzene in the Australian Petroleum Industry. Technical report and appendices. Monash University and Deakin University. Australia. 2001.
  5. Glass DC, Gray CN, Jolley DJ, et al. Leukemia risk associated with low-level benzene exposure. Epidemiology. 2003 Sep;14(5):569-577.
  6. Lan Q, Zhang L, Li G, et al. Hematotoxicity in workers exposed to low levels of benzene. Science. 2004 Dec 3;306(5702):1774-1776.
  7. Hayes RB, Yin SN, Dosemeci M, et al. Benzene and the dose-related incidence of hematologic neoplasms in China. Chinese Academy of Preventive Medicine--National Cancer Institute Benzene Study Group. J Natl Cancer Inst. 1997 Jul 16;89(14):1065-1071.
  8. Mehlman MA. Benzene: a haematopoietic and multi-organ carcinogen at any level above zero. Eur J Oncol. 2004;9(1):15-36.
  9. Glass DC, Gray CN, Jolley DJ, et al. Health Watch exposure estimates: Do they underestimate benzene exposure? Chem Biol Interact. 2005 May 30;153-154:23-32.
  10. Aksey JM. Aplastic Anemia due to benzol poisoning. Calif Western Med. 1928;29:262-263.
  11. Machle M. Gas intoxication. J Am Med Assoc. 1941;177:1965-1971.
  12. Flodin U, Fredriksson M, Persson B, et al. Acute myeloid leukemia and background radiation in an expanded case-reference study. Arch Environ Health. 1990 Nov-Dec;45(6):364-6.
  13. Santos-Mello R, Cavalcante B. Cytogenetic studies on gas station attendants. Mutat Res. 1992 Oct;280(4):285-90.
  14. Hogstedt B, Holmen A, Karlsson A, et al. Gasoline pump mechanics had increased frequencies and sizes of micronuclei in lymphocytes stimulated by pokeweed mitogen. Mutat Res. 1991 May;263(1):51-5.
  15. Oesch F, Fuchs J, Vaupel J, et al. DNA single strand break analysis in mononuclear blood cells of petrol pump attendants. Int Arch Occup Environ Health. 1995;67(1):35-9.
  16. Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute non-lymphocytic leukemia. Br Med J. 1978 Mar 4;1(6112):553.
  17. Infante PF, Schwartz E, Cahill R. Benzene in petrol: a continuing hazard. Lancet. 1990 Sep 29;336(8718):814-5.
  18. Jakobsson R, Ahlbom A, Bellander T, et al. Acute myeloid leukemia among petrol station attendants. Arch Environ Health. 1993 Jul-Aug;48(4):255-9.
  19. Schwartz E. Proportionate mortality ratio analysis of automobile mechanics and gasoline service station workers in New Hampshire. Am J Ind Med. 1987;12(1):91-9.
  20. Lindquist R, Nilsson B, Eklund G, et al. Acute leukemia in professional drivers exposed to gasoline and diesel. Eur J Haematol. 1991 Aug;47(2):98-103.
  21. Au WW, Ramanujam VMS, Ward JB, et al. Chromosome aberrations in lymphocytes of mice after sub-acute low-level inhalation exposure to benzene. Mutat Res. 1991 Jun;260(2):219-24.
  22. Ward JB, Ammenheuser MM, Ramanujam VMS, et al. The mutagenic effects of low level sub-acute inhalation exposure to benzene in CD-1 mice. Mutat Res. 1992 Jul;268(1):49-57.
  23. Patel AS, Talbott EO, Zborowski JV, et al. Risk of cancer as a result of community exposure to gasoline vapors. Arch Environ Health. 2004 Oct;59(10):497-503.
  24. Lindstrom AB, Highsmith VR, Buckley TJ. Gasoline-contaminated ground water as a source of residential benzene exposure: a case study. J Expo Anal Environ Epidemiol. 1994 Apr-Jun;4(2):183-95.

Dr. Brautbar is a board-certified internist and nephrologist, and certified in forensic medicine. If you are interested in retaining Dr. Brautbar for forensic and expert witness testimony services, please submit the Contact Form.


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