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Attachment to IRIS file for benzene, October 14, 1998


Carcinogenic Effects of Benzene: An Update

(EPA/600/P-97/001A, June 1997)

On June 30, 1997, the National Center of Environmental Assessment (NCEA), within the U.S. Environmental Protection Agency's Office of Research and Development, announced in the Federal Register (Fed. Reg. 62 (125): 35172-35173, 1997) the availability of a draft document entitled Carcinogenic Effects of Benzene: An Update (EPA/600/P-97/001A, June 1997) for a 60-day public review and comment period. The comment period closed August 29, 1997.

The FR notice also announced that Eastern Research Group, Inc. (ERG), an EPA contractor, would conduct a peer-review workshop on July 16, 1997, to review the draft document. An expert panel, consisting of six reviewers, was charged to review pertinent literature on the mode of action and carcinogenic effects of benzene. The panel was asked to determine whether new information that has become available since the 1985 interim quantitative cancer risk estimates due to inhalation of benzene would substantially modify the estimates of cancer risk contained in the earlier document. The panel members and their affiliations were as follows:

David Eastmond -- University of California, Riverside

David Hoel -- Medical University of South Carolina (chair)

George Kalf -- Jefferson Medical College, Thomas Jefferson University

Michele Medinsky -- Chemical Industry Institute of Toxicology

Robert Schnatter -- Exxon Biomedical Sciences, Inc.

Lauren Zeise -- California Environmental Protection Agency

Attendees at the workshop included representatives from industry, trade organizations, and EPA and other interested Federal agencies.

The summary report of the workshop entitled Report on the Expert Panel Peer Review of Benzene Risk Assessment Update (September 23, 1997) is available. The report included questions posed by EPA about the draft document and answers provided by the Peer Review Panel. The view of the panel members with respect to these questions is the basis of the summary report.

The following summarizes the comments received from the expert panel, and provides EPA's responses as reflected in the final document, Carcinogenic Effects of Benzene: An Update (EPA/600/P-97/001A, June 1997).


The peer-review panel complimented the Agency for the review draft document (EPA/600/P-97/001A dated June, 1997) and felt that the Agency did a very good job in covering the large body of scientific literature on the carcinogenic effects of benzene. The panel generally agreed that the abbreviated format and the focused discussion of the report provided a good overview of the current understanding of benzene's mode of action as well as the human risks associated with exposures to benzene. The panel further noted that the Agency focused on critical issues involved in developing a new potency estimate and has made an attempt to incorporate methodology consistent with the newly proposed cancer risk assessment guidelines.

The panel noted that the primary focus of the document should be on an assessment of the risk of benzene at environmental exposure levels and that the intent of the report should be more clearly stated. The panel questioned why the EPA's ongoing efforts to develop a non-cancer risk assessment of benzene are not being integrated into the report. The panel noted that a number of pertinent recent references had been omitted and should be added. The panel raised concern about the citation of unpublished information. The recommendation was to delete the citations that are not peer-reviewed. The panel was in agreement that many published epidemiologic studies indicate that benzene does not pose an increased risk of multiple myeloma and therefore the discussion should reflect this fact. The panel questioned the scientific evidence for benzene as a risk factor for leukemia cell types other than acute myeloid leukemia (AML) and recommended that the Agency should reflect this uncertainty. There was also substantial disagreement among the panelists regarding the use of non-linear versus linear extrapolation models to estimate cancer risk to humans at environmental levels. The panel agreed with EPA that the Pliofilm workers cohort (Rinsky et al., (1981, 1987), is the best available cohort for dose-response analysis and derivation of unit risk estimates for exposure to benzene. The panel also noted a recent publication containing dose-response information from the Chinese cohort (Hayes et al., 1997) and recommended discussing its use prior to releasing the final risk analysis. In addition, the panel raised the issue of the use exposure estimates of Rinsky et al (1981) and recommended that consideration be given to the use of the more recent exposure estimates of Paustenbach et al. (1992, 1993) rather than the Crump and Allen (1984) exposure estimates when calculating the unit risk. However, some panel members subsequently determined that these estimates were biased on the high side, while others disagreed.

The panel noted that ANLL provides the strongest basis for dose-response analysis and to characterize uncertainty, the potency estimated should be supplemented by those for all leukemia. In general, the discussion of the various modes of action of benzene was supported by the panel, but recommended that the Agency identify areas of significant controversies. There was agreement that the use of biologically-based modeling to estimate leukemia risk was premature. The panel members agreed that there were still considerable uncertainties and complexities regarding the mode of action of benzene. In general, the panel members felt that the document fairly presented the two contrasting perspectives that there is evidence that the leukemogenic effects of benzene exhibit a linear (non-threshold) as well as non-linear (threshold) response, and the Agency's decision to present both approaches and selection of linear model is consistent with the spirit of the proposed cancer risk assessment guidelines.

There was agreement among panel members that more scientific research is necessary to establish the shape of the dose-response curve, particularly, in the moderate to low-dose range.

The panel recommended that the Agency identify sensitive groups in the general population who may have differential exposure and differential risk. The panel complimented the Agency on the work it has done in bringing scientific considerations to the process of quantitative risk estimation.

EPA Responses

With regard to the panel members' recommendations for integrating the ongoing non-cancer risk assessment on benzene, the Agency intends in the near future to develop and integrate cancer with noncancer risk assessment and submit it to the Agency's Integrated Risk Information System (IRIS) process (Fed. Reg. 63 (1): 75-77, January 2, 1998).

The Agency agrees with the peer reviewers that all citations of unpublished literature should be eliminated and has done so. The peer reviewers have also recommended that several additional citations should be added. The Agency has included and discussed several additional studies.

The peer reviewers also noted that more recent epidemiological data indicates that multiple myeloma is no longer associated with exposure to benzene. Although multiple myeloma in earlier studies (Decoufle et al., 1983; Rinsky et al., 1981, 1987) was suggested as a consequence of exposure to benzene, this finding has not been substantiated in more recent epidemiological studies. The Agency agreed with the commenters and has changed the text to reflect this fact.

Some members of the panel questioned the scientific evidence for benzene as a risk factor for leukemia cell types other than AML. The evidence for assuming that other leukemia cell types are not associated with exposure to benzene is insufficient. The exact underlying mechanism(s) of leukemia induction from exposure to benzene is (are) not fully known (Smith and Fanning, 1997). There appears to be enough evidence in the literature to suggest that there may be more than one mechanism involved. Furthermore, the epidemiological evidence to date does not entirely support the concept that only the risk of AML is increased. Savitz and Andrews (1996) after reanalyzing the Rinsky et al (1981,1987) cohort by excluding AML found that the recalculated relative risk for the remaining aggregated three leukemic cell types was still elevated. On the other hand, recent studies (Hayes et al., 1997, Yin et al., 1996) have implicated exposure to benzene as responsible for an increase in the risk of non-Hodgkin's lymphoma as well as that of myelodysplastic syndrome and hematologic neoplasms. The Agency also does not believe that these data should be factored in at this time for derivation of the risk of exposure to benzene. Potential weaknesses in the Chinese cohort, as have been pointed out in the document, preclude its use in risk estimation.

There was substantial disagreement among the panelists regarding the use by the Agency of non-linear extrapolation models versus linear extrapolation models to estimate cancer risk to humans at environmental levels. The Agency has found that a current scientific consensus does not exist to support a decision to exclude either linearity or nonlinearity. The Agency has evaluated the evidence and concluded from published studies (Smith, 1996: Smith and Fanning, 1997) that the underlying mechanism(s) of leukemogenesis are too controversial to permit predicting the shape of the dose-response curve. Therefore, the Agency chose to use a linear response model as a default approach because no new data is available that will allow the Agency to proceed with a risk characterization using available exposure information.

The panel members agreed with the Agency that the best available cohort is still the Pliofilm workers (Rinsky et al. 1981, 1987) and it should be used to develop a dose-response analysis and derivation of unit risk estimates for exposure to benzene.. The panel members did feel that the Agency needed to better justify its use. The Agency agreed with the commenters and provided a better justification.

There was some disagreement amongst the panel members concerning which exposure estimates were the best to use for unit risk estimation. Some panel members preferred the exposure estimates of Rinsky et al., (1981), while others wanted the Agency to use Paustenbach's much higher exposure estimates (1992,1993. The Agency continued to rely on the exposure estimates of Crump and Allen, 1984 because they appear to be the least biased.

With respect to the recently published Chinese cohort, the Agency Reviewed the recent publications and has discussed these new findings in detail in the final document. Among cancer or related conditions that were found by the authors to be associated with exposure to benzene are non-Hodgkin's lymphoma, hematologic neoplasms and myelodysplastic syndromes as well as acute nonlymphocytic leukemia. Several of these conditions were found to be significantly elevated at 10 ppm-years. Several potential methodological problems exist that need to be resolved prior to its use in derivation of cancer unit risk estimates as discussed in the document. The Agency has provided in the text a detailed discussion of this study including its strengths and weaknesses.

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