Low Levels of Benzene and Hematopoietic Malignancies
NACHMAN BRAUTBAR, M.D.
Mealey's Benzene Litigation Conference
June 12-13, 2006
Marina del Rey, California
Benzene is a Known Human Carcinogen
While there is general consensus that benzene can cause leukemia, argument regarding "levels of exposure" that cause leukemia have been raging. [Literally, almost.]
Statement such as 20 to 40 ppm, 200 ppm, and 700 ppm "is required" (to be sufficient cause of leukemia) have been published by various investigators, industry-related experts, studies, and communication to OSHA.
Industry experts claim that there is a "certain" threshold for benzene below which leukemia "is not possible." [Contrary to regulatory agencies position that there is no known/safe level of exposure, and that benzene is a non-threshold carcinogen.]
Those claims are made despite and in the face of the still live and available on all web sites 1948 American Petroleum Institute publication that the safest level of exposure to benzene is no exposure. [Interesting enough, this paper has never been withdrawn by the API, suggesting that the 1948 statement is still "on."]
Regulatory Recommendations for Benzene Exposure:
- ATSDR: 0.05 ppm acute inhalation, 0.004 ppm intermediate risk level;
- ACGIH: TLV 0.5 ppm with a short-term exposure limit of 2.5 ppm;
- California EPA: No significant risk level, 13 μg/day (inhalation);
- NIOSH: 0.1 ppm short-term exposure;
- OSHA: permissible exposure limit 1 ppm, short-term: 5 ppm;
- Collegium Ramazzini: appealing for substantial reduction based on additional low levels exposure data; lowest level possible.
Dosimetry of Benzene Exposure
- For years dosimetry was expressed as cumulative ppm-years. 1 ppm x 40 years = 40 ppm-years [worker].
- If the worker is exposed to 1 ppm per day for 10 years, the cumulative exposure is 10 ppm-years.
- Several studies documented the importance of peak levels, intensity of exposure. For example, a major spill can cause peak exposure intensity of at least 8 ppm in one day, which can elevate the risk of leukemia compared to cumulative exposure. [Over and above the occupational daily exposure.]
- Indeed Shell in its presentations and categorization of exposures stated, "liquid visible and odor of benzene is present = 25-50 ppm." So that spills which are common in benzene processing, clearly create a substantial peak exposure, even in the hands of a refiner who tries to adheres to 1 ppm daily exposure. [Shell documents and communication]
- Therefore, cumulative peak exposure and exposure intensity are important in benzene dosimetry. It must be understood that cumulative exposure is expressed as ppm-years or ppb-years, and peak exposure levels as ppm or ppb per peak.
Evidence from Human Studies
- The Australian Study [Health Watch, 2000] described workers following 12 years of exposure to benzene. Average exposure level was 200 ppb (0.2 ppm), with an increase of leukemia risk, OR = 1.5 (95% CI = 1.02-2.15).
- Comparing OSHA's significant risk of 1:1000 benzene exposure for 45 years, the risk from the Australian Study of 3.5 deaths for 12.8 years translated based on OSHA standards to an OEL (observable effect level) of 16 ppb [Mehlman, Eur J Oncol. 2004]
- The chemical industry is well aware of peak exposure levels. The Monsanto Study [Collins et al., 2003] clearly stated, "we found little evidence with increasing cumulative exposure,� however peak exposures� showed increased SMR." Based on the study, Collins et al. concluded, "we find that high number of peak exposure to benzene is a better predictor of risk than cumulative exposure."
- The results of the Monsanto Study are confirmatory of the results of the Australian Study ; demonstrating that those workers who had a geometric "high intensity exposure between 0.8 and 1.56 ppm had a 7-fold increase in leukemia rate."
- The Glass Study  demonstrated an increased leukemia risk with benzene cumulative exposure at 2 ppm-years, as well as increased risk of leukemia with intensity of exposure starting at 0.8 - 1.6 ppm.
How Low Can We Go?
The recent Lan Study [Science, 2004] further supports the observations of Hayes , Glass , Collins , and Mehlman  by demonstrating substantial changes in white blood cell counts and progenitor colony formation at levels of 1 ppm or less. "These data provide evidence that benzene causes hematological effect at or below 1 ppm, particularly among susceptible subpopulation."
This table is adopted from the Lan Study [Science, 2004]:
- The most recent Glass Study  is a good summary of the studies regarding benzene dosimetry, "a strong association between leukemia and modest benzene exposure greater than 16 ppm-years (1 ppm x 16 years), expressed as cumulative exposure, or greater than 0.8 ppm intensity of highest exposed job."
- Ward et al.  examined red and white blood cells (WBC) from workers exposed to benzene, and found a strong exposure response. The authors concluded that there was no evidence of threshold for the hematological effects of benzene exposure, suggesting that even exposure at low levels of benzene (e.g., less than 5 ppm) may result in hematologic suppression.
- Zhang  examined white blood cells from workers exposed to benzene at an average concentration of 4.57 � 6.16 mg/m3 (1.43 � 1.93 ppm). Four hundred and thirty-seven workers were compared to 150 controls. With the increase in benzene concentration, Zhang found a lowering of white blood cell counts and an increase proportion of lymphocytic micronucleus, and concluded that low levels of benzene exposure is harmful to the exposed workers.
- Qu et al.  examined hematological indices in 130 exposed workers. Workers were monitored for benzene exposure; urinary metabolites and albumin adducts were among the biomarkers of exposure. An exposure dependent decline in both red blood cells and white blood cells was demonstrated at benzene concentration as low as 0.06 ppm (median of 3.2 ppm). At 0.5 ppm, the authors demonstrated significantly lower red blood cells and WBCs counts. The corresponding individual cumulative exposure duration and intensity (yearly average exposure level) were 14 years and 2.68 ppm. These studies demonstrate the hematotoxicity of benzene at both low levels of exposure and intensity of exposure.
Means and Standard Deviations for Blood Cell Counts, Grouped According to Average Lifetime Benzene Exposure Intensity (ppm per year)
*Means and standard deviations reported are the raw variables, but for the monocytes, eosinophils, and basophils, the statistical tests were performed on the log transformed data.
Levels as Low as 15 ppb Cumulative Exposure
- Industry has claimed over the years that cigarettes containing benzene and therefore inhalation of benzene in smokers is also a substantial factor.
- I agree for the following reasons:
- IARC, in its 2004 monograph on cigarette smoke and secondhand smoke states, "myeloid leukemia in adults was observed to be causally related to smoking. Support for this causative effect of cigarette smoking and leukemia is that cigarette smoke contains leukemogens such as benzene which is present in sufficient amount to account for half of the estimated excess of leukemia. [IARC. Monograph, 2004. Vol. 83. Page 1183]
- The average smoker of 1 pack/day for 20 years, has been calculated to inhale 15 ppb/years from cigarette smoke [NICNAS. Benzene. Priority Existing Chemical Assessment Report No. 21. Commonwealth of Australia. 2001]. So that 15 ppb is comparable to the calculations of Dr. Mehlman [Mehlman M. Eur J Oncol. 2004] and the Australian Study [Health Watch. Eleventh Report 2000], and Glass Studies [2003, 2005].
- Recent studies have shown increased risk for leukemias and lymphomas and cigarette smoking, further supporting the low level exposure.
- While criticism has been lodged at some industry experts (Wong, Paustenbach), the time does not allow me today to get into the individual criticisms, other than to remember Professor John Bailar's paper that "industry is commonly the one who somehow is able to get negative studies." Those negative studies must be scrutinized since some of those studies diluted population samples and failed to accurately estimate incidence and risk of leukemias.
Application to Benzene Cases
- Low levels of exposure as low as 15 ppb.
- Cumulative exposure levels of less than 10 ppm.
- Peak levels of exposure [much more damage to the hematopoietic system].
- Benzene exposure occur at both industrial and nonindustrial settings, each exposure is a substantial factor in causation of leukemia [substantial factor definition under California Supreme Court decision in Rutherford (Thelma L. Rutherford, et al. v. Owens-Illinois, Inc. Supreme Court of California. No. S046944. Decided August 28, 1997. 16 Cal. 4th 953).: not theoretical, rhetorical, or infinitesimal.
- Scientifically, an expert does not need to trace each "molecule" origin, other than substantial exposure.
So Which Benzene Caused the Leukemia? The Benzene in Downtown L.A. or My Clients' Benzene?
- This is a common question addressed in causation analysis.
- Under California law (Thelma L. Rutherford, et al. v. Owens-Illinois, Inc. 1997. 16 Cal. 4th 953), one does not need to prove that exposure to a particular defendants' product actually caused his cancer, but needs only to show defendants' product (in this case, benzene) was a substantial factor in increasing the risk of developing cancer.
- Exposure to benzene should be evaluated based on cumulative and peak exposure intensity of exposures;
- Benzene is hematotoxic at levels below 1 ppm;
- There is no evidence of "safe threshold levels" when it comes to benzene exposure.
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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